This study examined the efficacy and tolerability of duloxetine 60–120 mg/day for the treatment of patients with generalized anxiety disorder. This was a multicenter, randomized, double-blind, flexible-dose, placebo and active-controlled (venlafaxine extended-release 75–225 mg/day) trial designed to assess duloxetine 60–120 mg/day during 10 weeks of treatment in adults with Diagnostic and statistical manual of mental disorders-IV-defined generalized anxiety disorder. The primary efficacy outcome measure was mean change from baseline to endpoint in the Hamilton Anxiety Rating Scale total score assessed using analysis of covariance. A total of 487 patients were randomly assigned to duloxetine (n=162), venlafaxine XR (n=164), or placebo (n=161). Significantly greater improvement on the Hamilton Anxiety Rating Scale total score occurred in the duloxetine (P=0.007) and venlafaxine XR (P<0.001) groups compared with the placebo group. Overall discontinuation rates did not differ among the three groups, but adverse event-related discontinuation was significantly higher in the duloxetine (14.2%, P<0.001) and venlafaxine XR (11.0%, P=0.001) groups than in the placebo group (1.9%). During the 2-week drug-tapering phase, discontinuation-emergent adverse events were significantly greater in the venlafaxine XR group (26.9%, P=0.04), but not in the duloxetine group (19.4%, P=0.448) compared with placebo (15.8%). Duloxetine 60–120 mg/day and venlafaxine XR 75–225 mg/day were each efficacious treatments for patients with generalized anxiety disorder.