PURPOSE: We compared the effects of a eucaloric moderate-fat diet (18% protein, 36% fat, and 46% carbohydrate), a eucaloric low-fat high-carbohydrate diet (18% protein, 18% fat, and 64% carbohydrate), and a low-calorie (33% reduced) low-fat high-carbohydrate diet on biomarkers of systemic inflammation. METHODS: We randomly assigned 102 participants (age 21-76 years and BMI 19.2-35.5 kg/m(2)) to the three different diets for 6 weeks in a parallel design intervention trial. All foods were provided. Ninety-three participants completed all study procedures; 92 were included in the analyses. Endpoints included plasma C-reactive protein (CRP), interleukin-6 (IL-6), soluble tumor necrosis factor receptors I and II (sTNFRI and II), and adiponectin. RESULTS: In the unadjusted primary analyses, none of the endpoints were differentially affected by the dietary interventions despite the significantly greater reductions in body weight and fat mass in participants consuming the low-calorie low-fat diet compared to the eucaloric diets (p < 0.001). When including weight change in the model in secondary analysis, adiponectin tended to be increased with weight loss (time × weight change interaction, p = 0.051). Adjusted for weight change, adiponectin was reduced in the groups consuming the low-fat diets relative to the moderate-fat diet (p = 0.008). No effect of the intervention diets or weight loss on CRP, IL-6, or sTNFRI and II was seen in these secondary analyses. CONCLUSIONS: In relatively healthy adults, moderate weight loss had minimal effects on systemic inflammation, and raised plasma adiponectin only modestly. A lower dietary fat and higher carbohydrate content had little impact on measures of systemic inflammation, but reduced adiponectin concentrations compared to a moderate-fat diet. The latter may be of concern given the consistent and strong inverse association of plasma adiponectin with many chronic diseases.