Obesity is a risk factor for asthma. Adipose tissue expresses pro-inflammatory molecules including tumour necrosis factor (TNF), and levels of TNF are also related to polymorphisms in the TNF-alpha (TNFA) gene. The current authors examined the joint effect of obesity and TNFA variability on asthma in adults by combining two population-based studies. The European Community Respiratory Health Survey and the Swiss Cohort Study on Air Pollution and Lung and Heart Disease in Adults used comparable protocols, questionnaires and measures of lung function and atopy. DNA samples from 9,167 participants were genotyped for TNFA -308 and lymphotoxin-alpha (LTA) +252 gene variants. Obesity and TNFA were associated with asthma when mutually adjusting for their independent effects (odds ratio (OR) for obesity 2.4, 95% confidence interval (Cl) 1.7-3.2; OR for TNFA -308 polymorphism 1.3, 95% Cl 1.1-1.6). The association of obesity with asthma was stronger for subjects carrying the G/A and A/A TNFA -308 genotypes compared with the more common GIG genotype, particularly among nonatopics (OR for G/A and A/A genotypes 6.1, 95% Cl 2.5-14.4; OR for GIG genotype 1.7, 95% Cl 0.8-3.3). The present findings provide, for the first time, evidence for a complex pattern of interaction between obesity, a pro-inflammatory genetic factor and asthma.