**Background:** Non-communicable diseases, including cardiovascular disease (CVD), cancer, and diabetes, account for 4 of 5 deaths worldwide. The health effects of dietary fats remain highly controversial, with experts and authoritative organizations frequently disagreeing on optimal intake levels. While some guidelines recommend restricting total dietary fat to less than 30–35% of total energy intake, others conclude that total fat reduction has little effect on health outcomes. Existing systematic reviews on dietary fats have serious limitations: most address only one or a few health outcomes, whereas dietary recommendations require consideration of all patient-important outcomes; reviews often fail to present absolute effect estimates, which can lead to misinterpretation; only a handful have formally evaluated the certainty of evidence for each outcome; and none (aside from one guideline on red and processed meat) have used the GRADE fully contextualized approach. Additionally, the impact of missing participant outcome data on risk of bias has been inadequately addressed, despite evidence suggesting that almost one in three trials with statistically significant results lose significance when plausible assumptions are made about missing data.
**Methods:** This protocol describes a systematic review that will search MEDLINE, EMBASE, CINAHL, and the Cochrane Database of Systematic Reviews (CDSR) for RCTs addressing saturated fat and health outcomes. The search will be restricted to reviews published from 2015 onward, with an updated search for new primary studies from the date of the last comprehensive systematic review. Eligible RCTs must state an intention to reduce saturated fat intake or provide a dietary aim such as reducing total fat or improving heart health, while achieving a statistically significant (p < 0.05) reduction in saturated fat between intervention and control arms. Interventions must be low-fat dietary advice, supplementation with naturally occurring oils or fats, or provision of modified/low-fat foods, with a minimum intervention duration of 2 years (24 months). Trials that are formula-based, have pharmacological weight-loss interventions, or primarily aim to assess weight-loss will be excluded. Pairs of reviewers will independently screen, extract data, and assess risk of bias using a modified Cochrane risk of bias 1.0 instrument adapted for nutrition studies, with four response options and an index of suspicion (1 = definitely low risk to 4 = definitely high risk). Missing participant outcome data will be systematically assessed using a series of sensitivity analyses assuming event rate ratios of 1.5:1, 2:1, 3:1, and 5:1 in those with missing data compared to those successfully followed. For data synthesis, the review will conduct de novo meta-analyses comparing lower versus higher saturated fat intake, and saturated fat replaced with polyunsaturated fatty acids (PUFA), monounsaturated fatty acids (MUFA), protein, and complex carbohydrates. Depending on trial types, both standard pairwise comparisons and network meta-analysis may be performed. Absolute risks will be estimated using data from GLOBOCAN (for cancer outcomes over a lifetime) and the Emerging Risk Factors Collaboration (for cardiometabolic outcomes over 10.8 years). Effect magnitudes will be categorized using GRADE thresholds: for fatal outcomes, ≤10 events per 1000 is trivial, 11–25 per 1000 is small but important, and 26–40 per 1000 is moderate; for non-fatal outcomes, ≤20 per 1000 is trivial, 21–40 per 1000 is small but important, and 41–60 per 1000 is moderate. Subgroup analyses will examine effect modification by replacing macronutrient, type of intervention (food provision vs. advice only), co-interventions, change in LDL/total cholesterol, and risk of bias. The certainty of evidence will be assessed using the GRADE fully contextualized approach.
**Clinical Implications:** This systematic review aims to provide the most comprehensive and rigorous summary of evidence on saturated fat modification and patient-important health outcomes. By addressing all critical outcomes, using nutrition-specific risk of bias tools, calculating absolute effect estimates, and applying the GRADE fully contextualized approach, the findings will directly inform public health nutrition guidelines on saturated fat consumption. The evidence will support recommendations for individuals at very low, low, and high risk of cardiovascular events, and will be disseminated through peer-reviewed publication, conference presentations, GRADE summary of findings tables, plain language summaries, and infographics for clinicians, patients, and community members.