Baseline serum C-reactive protein (CRP) concentrations play a role in the lipid response to diet. This study was a randomized, cross-over, controlled feeding study with 3 phases of 25 d each aimed at determining whether baseline CRP concentrations modulate the serum lipid response to diets differing in fat type and quantity. Participants were adult men and women, age 19-65 y, with LDL-cholesterol concentrations of 3.37-4.66 mmol/L. All participants consumed 3 diets differing in the type of snack, either low or high in fat: low-fat (30.8% of energy), moderate in fat and saturated fat (37.9 and 11.4% of energy, respectively), or moderate in fat and polyunsaturated fat (36.3 and 9.7% of energy, respectively). Using baseline CRP as a continuous variable, CRP x diet interactions on change in serum lipoprotein_a (P = 0.045) and HDL-cholesterol (P = 0.06) were observed. When we used previously established categories to define CRP concentrations (low, <1 mg/L; intermediate, 1-3 mg/L; or high, >3 mg/L), we found a CRP x diet interaction on change in triglyceride concentrations (P = 0.03) and trends for CRP x diet interaction on change in LDL (P = 0.06) and total cholesterol (P = 0.07). If replicated, these results suggest that considering baseline CRP concentrations when prescribing dietary interventions to lower lipid concentrations may be useful. Individuals with high baseline CRP concentrations may benefit from moderate-fat, high polyunsaturated fat diets, whereas those with low baseline CRP concentrations may obtain greater lipid-lowering benefits from low-fat diets.