Background The rising trend in obesity calls for innovative weight loss programs. While behavioral-based face-to-face programs have proven to be the most effective, they are expensive and often inaccessible. Internet or Web-based weight loss programs have expanded reach but may lack qualities critical to weight loss and maintenance such as human interaction, social support, and engagement. In contrast to Web technologies, virtual reality technologies offer unique affordances as a behavioral intervention by directly supporting engagement and active learning. Objective To explore the effectiveness of a virtual-world weight loss program relative to weight loss and behavior change. Methods We collected data from overweight people (N = 54) participating in a face-to-face or a virtual-world weight loss program. Weight, body mass index (BMI), percentage weight change, and health behaviors (ie, weight loss self-efficacy, physical activity self-efficacy, self-reported physical activity, and fruit and vegetable consumption) were assessed before and after the 12-week program. Repeated measures analysis was used to detect differences between groups and across time. Results A total of 54 participants with a BMI of 32 (SD 6.05) kg/m2 enrolled in the study, with a 13% dropout rate for each group (virtual world group: 5/38; face-to-face group: 3/24). Both groups lost a significant amount of weight (virtual world: 3.9 kg, P < .001; face-to-face: 2.8 kg, P = .002); however, no significant differences between groups were detected (P = .29). Compared with baseline, the virtual-world group lost an average of 4.2%, with 33% (11/33) of the participants losing a clinically significant (≥5%) amount of baseline weight. The face-to-face group lost an average of 3.0% of their baseline weight, with 29% (6/21) losing a clinically significant amount. We detected a significant group × time interaction for moderate (P = .006) and vigorous physical activity (P = .008), physical activity self-efficacy (P = .04), fruit and vegetable consumption (P = .007), and weight loss self-efficacy (P < .001). Post hoc paired t tests indicated significant improvements across all of the variables for the virtual-world group. Conclusions Overall, these results offer positive early evidence that a virtual-world-based weight loss program can be as effective as a face-to-face one relative to biometric changes. In addition, our results suggest that a virtual world may be a more effective platform to influence meaningful behavioral changes and improve self-efficacy.