Objective:This study examined changes in mental health symptoms and weight during weight loss treatment. It was hypothesized that worsening mental health would negatively impact weight loss. Methods:Data were analyzed from a trial of 92 Hispanic women with overweight/obesity and prediabetes, who were randomized to receive intensive lifestyle intervention (ILI), metformin 1,700 mg daily, or standard care. Depression, anxiety and perceived stress were assessed at 0, 6 and 12 months. Six- and 12-month weight change was compared among participants whose symptom scores worsened on any mental health measure (W) vs. improved or remained stable on all three (I/S). Results:Among ILI participants, the 12-month difference in weight loss between I/S and W groups was statistically significant: -5.1 kg (P = 0.001). From baseline to 6 months, ILI participants in I/S and W groups experienced comparable weight loss. However, from 6 to 12 months, W participants regained weight, whereas I/S participants experienced continued weight loss. In the metformin and standard care arms, there was no weight difference between I/S and W groups. Conclusions:In ILI, 12-month improvement or stability in mental health was significantly associated with weight loss. Weight trajectories between I/S and W groups diverged at 6 months.