We investigated associations of markers of inflammation such as albumin, fibrinogen, C-reactive protein (CRP), and white blood cell count (WBCC) with future weight gain and weight loss in middle-aged adults in order to further elucidate the relationship between subclinical inflammation and weight change. Data were derived from the third population-based MONICA (Monitoring of Trends and Determinants in Cardiovascular Diseases) Augsburg survey (S3) conducted as part of the multinational World Health Organization MONICA project in 1994-1995 and a follow-up examination, to which all eligible subjects from S3 were invited in 2004-2005 (F3). In total, 2,792 persons (1,391 men, 1,401 women) aged 25-74 years at baseline were analyzed. Subjects with elevated concentrations of inflammatory markers were more prone to gain weight during follow-up. The odds ratios (OR) for a large mean annual weight gain (i.e., on average 1.02 kg/year) was 1.73 (95% confidence interval (CI) 1.27, 2.35) in fully adjusted analyses for subjects in the highest compared to the lowest quartile of fibrinogen. The respective ORs were 1.45 (95% CI, 1.08, 1.94) and 1.37 (95% CI, 1.03, 1.82) for CRP and WBCC. Stratified analyses revealed that associations were strongest among subjects who quitted smoking during the follow-up period (new quitters). Associations of inflammatory markers with large mean annual weight loss were weaker and became nonsignificant after multivariable adjustment. In conclusion, elevated levels of inflammatory markers are independently associated with weight gain in middle-aged adults, particularly among new quitters. This suggests that inflammation plays a key role in the process of weight gain, especially after smoking cessation.