BACKGROUND: Lifestyle interventions are efficacious at reducing risk for diabetes and cardiovascular disease but have not had a significant public health impact given high cost and patient and provider burden. OBJECTIVE: Online social networks may reduce the burden of lifestyle interventions to the extent that they displace in-person visits and may enhance opportunities for social support for weight loss. METHODS: We conducted an iterative series of pilot studies to evaluate the feasibility and acceptability of using online social networks to deliver a lifestyle intervention. RESULTS: In Study 1 (n=10), obese participants with depression received lifestyle counseling via 12 weekly group visits and a private group formed using the online social network, Twitter. Mean weight loss was 2.3 pounds (SD 7.7; range -19.2 to 8.2) or 1.2% (SD 3.6) of baseline weight. A total of 67% (6/9) of participants completing exit interviews found the support of the Twitter group at least somewhat useful. In Study 2 (n=11), participants were not depressed and were required to be regular users of social media. Participants lost, on average, 5.6 pounds (SD 6.3; range -15 to 0) or 3.0% (SD 3.4) of baseline weight, and 100% (9/9) completing exit interviews found the support of the Twitter group at least somewhat useful. To explore the feasibility of eliminating in-person visits, in Study 3 (n=12), we delivered a 12-week lifestyle intervention almost entirely via Twitter by limiting the number of group visits to one, while using the same inclusion criteria as that used in Study 2. Participants lost, on average, 5.4 pounds (SD 6.4; range -14.2 to 3.9) or 3.0% (SD 3.1) of baseline weight, and 90% (9/10) completing exit interviews found the support of the Twitter group at least somewhat useful. Findings revealed that a private Twitter weight-loss group was both feasible and acceptable for many patients, particularly among regular users of social media. CONCLUSIONS: Future research should evaluate the efficacy and cost-effectiveness of online social network-delivered lifestyle interventions relative to traditional modalities.