Both obesity rates and antidepressant use have escalated in the last 20 years. Most people who start antidepressant treatment discontinue it on their own. Meanwhile, obesity rates continue to increase. To test the hypothesis that antidepressant use is a risk factor for obesity, even after long-term discontinuation, we developed a novel animal paradigm consisting of short-term exposure to stress and antidepressants, followed by long-term high-fat diet. We show here that recurrent restraint stress (RRS)-related weight loss is recovered 2 weeks after the end of stress in young growing rats receiving a high-fat diet. It is noteworthy that animals that received short-term antidepressant treatment with either imipramine or fluoxetine during 7 days of RRS showed behavioral evidence of antidepressant effects. When exposed to a high-fat diet after stress and when antidepressant treatment had ended, the animals had significant increases in caloric intake, body weight (BW) and size from 17 to 22 weeks following antidepressant discontinuation when compared with (control) RRS animals treated with saline and fed with a high-fat diet. These data are consistent with the previously described phenomenon of time-dependent sensitization, and support the notion that enduring effects of short-term antidepressant treatment become manifest on a long-term basis after antidepressant discontinuation, during conditions of high stress followed by high-fat intake. Analyses of open field and body size measurements obtained in a small subset of animals show that animals previously exposed to antidepressant had no deficits in locomotor activity and were larger. Antidepressant exposure may therefore be a covert, insidious and enduring risk factor for obesity, even after discontinuation of antidepressant treatment. Our data support the concept of persistent, long-term effects of pharmacological-environment interactions on BW regulation.