The risk of weight gain is an important determinant of the acceptability and tolerability of antidepressant medication. To compare changes in body weight during treatment with different antidepressants, body weight and height were measured at baseline and after 6, 8, 12 and 26 wk treatment with escitalopram or nortriptyline in 630 adults with moderate-to-severe unipolar depression participating in GENDEP, a part-randomized open-label study. Weight increased significantly more during treatment with nortriptyline compared to escitalopram. The weight gain commenced during the first 6 wk of nortriptyline treatment, reached on average 1.2 kg at 12 wk (0.44-point BMI increase), and continued throughout the 6-month follow-up period. Participants who were underweight at baseline gained most weight. Participants who were obese at baseline did not gain more weight during treatment. Weight gain occurred irrespective of whether weight loss was a symptom of current depressive episode and was identified as an undesired effect of the antidepressant by most participants who gained weight. There was little weight change during treatment with escitalopram, with an average increase of 0.14 kg (0.05-point BMI increase) over 12 wk of treatment. In conclusion, treatment with the tricyclic antidepressant nortriptyline was associated with moderate weight gain, which cannot be explained as a reversal of symptomatic weight loss and is usually perceived as an undesired adverse effect. While treatment with nortriptyline may be recommended in underweight subjects with typical neurovegetative symptoms, escitalopram is a suitable alternative for subjects at risk of weight gain.