Objectives: The present study aimed at investigating the effectiveness and tolerability of -bupropion hydrochloride extended release (XL) in major depressive disorder (MDD) patients with atypical features (AF). Methods: 51 patients were prescribed bupropion XL for 8 weeks (6 visits: screening, baseline, weeks 1, 2, 4 and 8). The primary efficacy measure was a change of the Structured Interview Guide for the Hamilton Depression Rating Scale-Seasonal Affective Disorder Version (SIGH-SAD) from baseline to endpoint. Secondary efficacy measures included the SIGH-SAD atypical symptoms subscale, Clinical Global Impression-Severity (CGI-S), Sheehan Disability Scale (SDS) and Epworth Sleepiness Questionnaire (ESQ). Response or remission was defined as >= 50% reduction or <= 7 in SIGH-SAD total scores, respectively, at end of treatment. Results: The HAM-D-29 total score reduced by 55.3% from baseline (27.3 +/- 6.5) to end of treatment (12.2 +/- 6.3) (p<0.001). Atypical symptom subscale scores also reduced by 54.5% from baseline (9.2 +/- 3.0) to end of treatment (4.2 +/- 2.8) (p<0.001). At the end of treatment, 24.4% (n=10) and 51.2% (n=21) subjects were classified as remitters and responders, respectively. The most frequently reported AEs were headache (13.7%), dry mouth (11.8%), dizziness (9.8%), and dyspepsia (9.8%). Conclusions: Our preliminary study indicates that bupropion XL may be beneficial in the treatment of MDD with atypical features. Adequately powered, randomized, double-blind, placebo-controlled trials are necessary to determine our results.