Change in high-sensitivity C-reactive protein (CRP) from low-fat diet (diet) and physical activity (PA) interventions is relatively unknown for adults with metabolic syndrome. The objective of the study was to assess CRP change (DeltaCRP) with diet and/or PA in men and women with and without metabolic syndrome. Men (n = 149) and postmenopausal women (n = 125) with elevated low-density lipoprotein cholesterol and low high-density lipoprotein cholesterol were recruited into a 1-year randomized controlled trial. Treatment groups were as follows: control, diet (reduced total fat, saturated fat, and cholesterol intake), PA (45-60 minutes at 60%-85% maximum heart rate), or diet + PA. Weight loss was not an intervention focus. Metabolic syndrome was defined using the American Heart Association/National Heart, Lung, and Blood Institute criteria. Stored plasma samples were analyzed for CRP. Change in CRP was compared between treatments, within sex and metabolic syndrome status, using analysis of covariance, including covariates for baseline CRP and body fat change. For women with metabolic syndrome (n = 39), DeltaCRP was greater in diet vs control (-1.2 +/- 0.4, P = .009), diet + PA vs control (-1.3 +/- 0.4, P = .006), and diet + PA vs PA (-1.1 +/- 0.4, P = .02). Women with metabolic syndrome receiving the diet component (diet or diet + PA) had greater DeltaCRP compared with those who did not (control or PA) (P = .001). Change in CRP was not significantly different between intervention groups in men overall, women overall, men with (n = 47) or without metabolic syndrome (n = 102), or women without metabolic syndrome (n = 86). Low-fat diet may be the most effective treatment for reducing CRP in women with metabolic syndrome.