Background: Obesity is associated with elevated levels of estrogen. Gastric bypass causes rapid weight loss and decreased levels of estrogen. Patients after gastric bypass can suffer from anxiety and depression out of proportion to the surgical outcome. This study reports the efficacy of a short-term empiric trial of topical estradiol for the treatment of mild to moderate depression and anxiety following mini-gastric bypass (MGB) in women. Methods: Postoperative MGB women were surveyed for the presence of depressive symptoms before and after MGB. The results of an empiric trial of transdermal patches of estradiol-17β were assessed. Outcome measures were the self-reported efficacy of the patch. Results: 711 women who had undergone MGB and had functioning e-mail addresses made up the study. 62% of patients reported depression prior to surgery. 156 patients (22%) reported depression after the operation. 130 women were treated empirically with the patch, and remission of depression was observed in 92 (71%). In response to the question "Did the estrogen patch help?", subjects reported responses of 1) Yes, fantastic, 2) Yes, somewhat, 3) Hard to say, 4) No, in 36%, 31%, 20%, 13% of respondents respectively. Patients treated with estradiol sustained antidepressant benefit of treatment after the patch was discontinued. Treatment lasted <1 month, 1-3 months, and >3 months, in 48%, 32% and 20% respectively. Treatment was well-tolerated and adverse events were rare. Conclusion: Depression is common in obese patients and remains a problem in a subset following the MGB operation. Transdermal estradiol replacement appears to be an effective treatment of symptoms of depression in women following MGB.