Small intervention studies suggest that modest weight loss increases the chance of conception and may improve perinatal outcome, but large randomized controlled trials (RCT) are lacking. Our objective was to investigate the effects of a lifestyle intervention in obese infertile women in a multicenter RCT. We randomly assigned infertile women with body mass index ≥ 29 k/m² to a six-month lifestyle intervention preceding infertility treatment or to prompt infertility treatment. The primary outcome was the vaginal birth of a healthy singleton at term within 2 years of randomization. Between June 2009-June 2102 we randomly allocated 577 women to one of two treatment strategies: 290 to lifestyle intervention preceding infertility treatment (intervention group) and 287 to prompt infertility treatment (control group). Three women withdrew informed consent, leaving 289 and 285 women for analysis. Discontinuation rate during the lifestyle intervention was 22%. Mean weight loss in the intervention group was 4.4 kg and in the control group 1.1 kg ( p < 0.001); the primary outcome occurred in 76 women (27%) in the intervention group versus 100 (35%) in the control group (RR: 0.77, 95% CI 0.60 to 0.99). The number of natural conceptions leading to ongoing pregnancies was 73 (26%) versus 46 (16%) (RR: 1.6, 95% CI 1.2 to 2.2). Maternal pregnancy-related and labor-related complications and neonatal complications were comparable. In obese infertile women lifestyle intervention preceding infertility treatment did not result in better rates of vaginal birth of healthy singletons at term as compared to prompt infertility treatment.