Background. Major depressive disorder (MDD) is associated with significant impairment in occupational functioning. This study sought to determine which depressive symptoms and medication side effects were perceived by patients with MDD to have the greatest interference on work functioning. Methods. 164 consecutive patients with MDD by DSM-IV criteria completed a standard assessment that included a self-rated questionnaire about the degree to which symptoms and side effects interfered with work functioning. Results. The symptoms perceived by patients as interfering most with work functioning were fatigue and low energy, insomnia, concentration and memory problems, anxiety, and irritability. The medication side effects rated as interfering most with work functioning were daytime sedation, insomnia, headache, and agitation/anxiety. There were no differences between men and women in symptoms or side effects that were perceived as interfering with work functioning. Limitations. This was a cross-sectional study; only subjective assessments of work functioning were obtained; the fact that patients were using varied medications acts as a potential confound. Conclusions. Specific depressive symptoms and medication side effects were perceived by patients as interfering more with occupational functioning than others. These factors should be considered in treatment selection (e.g., in the choice of antidepressant) in working patients with MDD.