© 2014 by the American Diabetes Association. OBJECTIVE To determine whether an intensive lifestyle intervention (ILI) designed to sustain weight loss and improve physical fitness in overweight or obese persons with type 2 diabetes was associated with bone loss after 4 years of follow-up.RESEARCH DESIGN AND METHODS This randomized controlled trial of intensive weight loss compared an ILI with a diabetes support and education (DSE) group among 1,309 overweight or obese subjects. Bone mineral density was assessed at baseline and after 1 year and 4 years of intervention.RESULTS ILI was effective in producing significant weight loss (5.3% vs. 1.8% in ILI and DSE, respectively; P < 0.01) and increased fitness (6.4% vs.20.8%) at year 4. Inmen, ILI participants had a greater rate of bone loss during the first year (21.66% vs. 20.09% per year in ILI and DSE, respectively). Differences between groups were diminished by one-half after 4 years (20.88% vs. 20.05% per year in ILI and DSE, respectively) but remained significant (P < 0.01). The difference in rate of hip bone loss between groups over 4 years was related to increased weight loss in ILI. Among women, the rate of bone loss did not differ between ILI and DSE after 4 years.CONCLUSIONS A 4-year weight loss intervention was significantly associated with a modest increase in bone loss at the hip in men but not in women.