C-reactive protein (CRP) is associated with increased risk for cardiovascular disease and diabetes. Few studies have evaluated the importance of CRP in those with the cluster of cardiovascular risk factors known as the metabolic syndrome (MS). We studied 190 overweight subjects (83 men and 107 women), aged 25-75 years, screened for glucose intolerance, in order to assess whether CRP levels vary according to the presence of MS, and to examine the relationship between CRP levels and metabolic variables. The prevalence of the Adult Treatment Panel III MS was 36.8%. Subjects with the MS had a higher degree of insulin resistance (IR), measured by the homeostasis model assessment (HOMA) method (5.4+/-0.4 versus 3.6+/-0.3, p<0.001) and higher frequency of glucose intolerance (78.3% versus 44.4%, p<0.001) than those without the MS. CRP values were increased among those with the MS (4.85+/-0.47 mg/l versus 3.34+/-0.36 mg/l, p<0.05). CRP correlated with waist circumference (r=0.28, p<0.001) and body mass index (r=0.38, p<0.001) in both men and women; however the relationship of CRP with HOMA(IR) was only evident in men (r=0.37, p<0.01) while the association with free fatty acids (FFA) was only significant in women (r=0.20, p<0.05), even after adjusting for age, hispanic ethnicity and glucose tolerance status. Abdominal obesity (elevated waist circumference) was the single most important MS component associated with increased CRP levels (>3mg/dl) (OR=3.1, 95% C.I.: 1.4-10.1), followed by female gender and smoking. These results confirm that CRP levels are elevated in MS subjects at risk for glucose intolerance. In addition waist circumference, HOMA(IR) and FFA levels are associated with CRP levels, suggesting potential roles of obesity, insulin resistance and lipolysis in the development of the subclinical inflammation associated with the MS.