Up to 50% of patients with major depressive disorder (MDD) fail to respond to an antidepressant trial, with most taking a selective serotonin reuptake inhibitor (SSRI) as an initial treatment. Switching to bupropion, for depressed patients not responding to SSRIs, is a popular strategy among clinicians. This study assesses the efficacy of bupropion SR in the management of MDD resistant to a prospective trial of fluoxetine. Twenty-nine patients with MDD refractory to an 8- to 12-week open-trial of fluoxetine were enrolled in an 8-week open-trial of bupropion SR. Both a completer analysis (n = 20) and a modified intent-to-treat analysis (n = 26) were performed to evaluate bupropion SR response rates. Using a completer analysis, seven patients (35.0%) were classified as responders, five (25.0%) partial responders, and eight (40.0%) nonresponders. A modified intent to treat analysis resulted in nine (34.6%) patients classified as responders, eight (30.8%) partial responders, and nine (34.6%) nonresponders. The overall proportion of remitters was 6/20 (30.0%) using a completer analysis and 6/26 (23.1%) using an MITT analysis. Approximately 60% of patients with MDD resistant to a prospective trial of fluoxetine experienced a full or partial response to bupropion SR. Bupropion SR should be considered as a potential treatment for patients who remain depressed despite treatment with SSRIs