Rapid weight gain in childhood is associated with increased risk of chronic diseases in adults. C‐reactive protein (CRP) is a mediator of atherosclerosis and chronically elevated levels predict cardiovascular outcomes. The effects of life course weight gain on CRP levels are not clear. The 1982 Pelotas (Brazil) birth cohort study (n = 5,914) has prospectively collected weight and health data at several follow‐ups since birth. The most recent was in 2004–05, when 77.4% of the cohort was traced and CRP levels were measured in 89% of those interviewed (n = 3827). Geometric mean (SE) C‐reactive protein levels were 0.89 mg/l (0.03) and 1.66 mg/l (0.04) in men and women, respectively. In analyses adjusted for confounding variables, weight gain in infancy showed a weak negative association among males, but from the second year onwards, weight gain was positively associated with CRP levels. In females, weight gain was associated with higher CRP at every period tested. The strongest associations were observed in the most recent (18–23 years) period; CRP ratios (95% CI) per z score increase in weight gain were 1.78 (1.57–2.00) and 1.52 (1.30–1.78) for men and women, respectively. Males who were stunted at 2 years and centrally obese at 23 years had the highest CRP levels (P = 0.002 for interaction). In summary, rapid weight gain throughout life predicted higher CRP levels. Public health efforts need to tackle chronic under‐nutrition in infancy, together with rapid weight gain in later childhood and adolescence, especially in countries undergoing the nutritional transition. Am. J. Hum. Biol. 2009. © 2008 Wiley‐Liss, Inc.