Low-grade systemic inflammation is associated with an increased risk of type 2 diabetes mellitus. Limited available data suggest inflammatory factors are predictive of gestational diabetes (GDM), a condition that is biochemically similar to type 2 diabetes. We examined the association between C-reactive protein (CRP) and GDM risk. Women were recruited before 16 weeks gestation and were followed until delivery. Maternal serum CRP (collected at 13 weeks' gestation, on average) was measured by a competitive immunoassay. We used generalised linear models to derive estimates of relative risks and 95% confidence intervals [CI]. Approximately 4.5% of the cohort (38 of 851) developed GDM. Elevated CRP was positively associated with GDM risk (P for trend = 0.007). After adjusting for maternal prepregnancy body mass index (BMI), family history of type 2 diabetes and nulliparity, women with CRP in the highest tertile experienced a 3.5-fold increased risk of GDM [95% CI 1.2, 9.8] as compared with those in the lowest tertile. The association between CRP and GDM was evident when analyses were restricted to lean women (BMI < 25 kg/m(2)). Lean women with CRP > or = 5.3 mg/L experienced a 3.7-fold increased risk of GDM [95% CI 1.6, 8.7] as compared with women with CRP < 5.3 mg/L. Systemic inflammation is associated with an increased risk of GDM, and the association is independent of maternal prepregnancy adiposity.