Obesity is a prevalent health condition that affects 14% to 20% of women of reproductive age. Some of the adverse affects of obesity on reproductive health include increased risks of menstrual dysfunction, anovulation, and infertility, especially resulting in failure of assisted reproductive techniques. There are various guidelines that advocate lifestyle intervention programs aimed at weight loss of 5% to 10% of body weight as the first step in caring for obese infertile women. There is, however, a dearth of randomized controlled trials assessing the effectiveness of lifestyle intervention programs. The objective of this study was to assess the effectiveness of a lifestyle intervention preceding infertility treatment. A multicenter randomized trial was conducted at 6 university medical centers and 17 general hospitals in the Netherlands. Infertile women with a body mass index (the weight in kilograms divided by the square of the height in meters) of 29 or higher were randomly assigned to a 6-month lifestyle intervention program preceding treatment for infertility or to prompt treatment for infertility. Primary outcome was the vaginal birth of a healthy singleton at term within 24 months after randomization. Prespecified secondary outcomes included a change in the woman's weight, waist circumference, and blood pressure. The participants were assigned to 2 treatment groups. A total of 290 women were assigned to a 6-month lifestyle intervention program preceding 18 months of infertility treatment (intervention group), and 287 were assigned to prompt infertility treatment for 24 months (control group of which 3 women withdrew consent, resulting in 289 women in the intervention group and 285 women in the control group). The study revealed that in intention-to-treat analyses, the mean weight loss was 4.4 kg in the intervention group and 1.1 kg in the control group (P < 0.001). Whereas the primary outcome occurred in 27.1% of the women in the intervention group, it was 35.2% in the control group (rate ratio in the intervention group, 0.77; 95% confidence interval, 0.60–0.99). The findings of the study show that in obese infertile women, a lifestyle intervention preceding infertility treatment, as compared with prompt infertility treatment, did not result in higher rates of a vaginal birth of a healthy singleton at term within 24 months after randomization.