This study examined the combination of sertraline, a selective serotonin reuptake inhibitor, and relapse prevention training in the maintenance of weight loss following treatment by a very-low-calorie diet. A total of 53 women who had lost a mean (+/- SD) of 22.9 +/- 7.1 kg from a pretreatment weight of 103.1 +/- 17.8 kg were randomly assigned to a 54-week weight maintenance program that was combined with either: 1) 200 mg/d of sertraline; or 2) placebo. During the first 6 weeks, sertraline subjects lost significantly more weight and reported significantly greater reductions in hunger and preoccupation with food than did subjects on placebo. After this time, however, women in both conditions regained weight steadily. The 13 sertraline subjects who completed the 54-week study regained 17.7 +/- 10.6 kg of their original 26.3 +/- 7.6 kg loss, equal to a regain of 70.9 +/- 41.7%. The 17 placebo completers regained 11.8 +/- 9.0 kg of their 23.4 +/- 7.8 kg loss, equal to a 46.5 +/- 34.6% regain. End-of-treatment differences between groups in weight change were not statistically significant. Nor were there significant differences between the two conditions at any time in changes in fat-free mass, resting metabolic rate or dysphoria, all of which tended to increase with weight regain. The results are discussed in relation to findings from other long-term studies that combined diet and medication.