Context: Obesity is associated with low-grade inflammation, but the long-term effects of weight change on inflammation are unknown. Objective: The aim was to examine the association of change in weight, body mass index (BMI), and waist circumference with change in C-reactive protein (CRP) and IL-6 and to assess whether this association is modified by baseline obesity status. Design and Setting: The design was a prospective cohort study among civil servants (the Whitehall II Study, UK). We used data from two clinical screenings carried out in 1991–1993 and 2002–2004 (mean follow-up, 11.3 yr). Participants: We studied 2496 men and 1026 women [mean age, 49.4 (sd = 6.0) yr at baseline] with measurements on inflammatory markers and anthropometry at both baseline and follow-up. Main Outcome Measures: We measured change in serum CRP and IL-6 during follow-up. Results: The mean increases in CRP and IL-6 were 0.08 [95% confidence interval (CI), 0.07–0.09] mg/liter and 0.04 (95% CI, 0.03–0.05) pg/ml per 1-kg increase in body weight during follow-up. Study members with a BMI less than 25 kg/m2 at baseline had an average increase in CRP of 0.06 (95% CI, 0.05–0.08) mg/liter per 1-kg increase in body weight, whereas the increase in those who were overweight (25 ≤ BMI < 30 kg/m2) and obese (BMI ≥30 kg/m2) was greater: 0.08 (95% CI, 0.06–0.09) mg/liter and 0.11 (95% CI, 0.07–0.14) mg/liter, respectively (P value for interaction = 0.002). Similar patterns were observed for changes in BMI and waist circumference. Conclusions: Those who were overweight or obese at baseline had a greater absolute increase in CRP per unit increase in weight, BMI, and waist circumference than people who were normal weight.