ABSTRACT: The role of saturated fatty acids (SFAs) in chronic disease remains controversial; inflammation is one pathway by which SFAs influence the risk for chronic disease. The aim of this study was to investigate the associations between red blood cell (RBC) phospholipid SFAs and systemic inflammation.As part of a randomized controlled trial, we measured RBC phospholipid FA composition in 55 generally healthy adults twice at 3-mo intervals. We estimated associations of RBC total SFAs and two major SFA subtypes, palmitic and stearic acids, with C-reactive protein (CRP), interleukin (IL)-6, white blood count (WBC), and a composite inflammation measure using generalized estimating equations in multivariable FA substitution models.Mean (±SD) SFA level across both visits was 45% ± 3% of the total RBC FAs, mainly palmitic (21% ± 1%) and stearic (17% ± 3%) acids. In models adjusted for age, sex, race, smoking, body mass index, statin use, aspirin use, transunsaturated FAs, and ?-3 FAs, SFAs were significantly associated with IL-6 (20% increase per 1 SD increment; 95% confidence interval [CI], 0.03%-43%; P = 0.05) and the composite inflammation measure (P = 0.05) and marginally associated with CRP (34% increase; 95% CI, -1% to 81%; P = 0.06), but not associated with WBC. Stearic acid was positively associated with CRP (35% increase; 95% CI, 2%-79%; P = 0.04). Palmitic acid was marginally associated with the composite inflammation measure (P = 0.06) and, upon additional ?-6 FA adjustment, significantly associated with IL-6 (15% increase; 95% CI, 0.4%-27%; P = 0.006).RBC SFAs, which represent longer-term dietary intake, are positively associated with inflammation. In particular, palmitic acid was associated with IL-6, and stearic acid was associated with CRP after multivariable adjustment.