1. This was a randomized, double-blind comparison of the efficacy and safety of venlafaxine and fluoxetine in outpatients with major depression. 2. Three hundred fourteen patients were randomly assigned to either venlafaxine 37.5 mg twice daily or fluoxetine 20 mg once daily for a maximum of 8 weeks. 3. If the response was inadequate after two weeks of treatment, the dosage of venlafaxine could be increased to 75 mg twice daily. 4. A clinical response, defined as at least a 50% decrease from baseline in the total HAM-D score, was attained at week 6 in 72% of patients on venlafaxine and 60% of patients on fluoxetine (p = 0.023). 5. Among patients who increased their dose at 2 weeks, venlafaxine was significantly (p < 0.05) superior from week 3 onward on the HAM-D. 6. Venlafaxine 75 mg daily is comparable to fluoxetine, but at 150 mg daily, it may be superior to fluoxetine in outpatients with major depression who do not respond early to treatment.