The objective of this study was to evaluate the anxiolytic efficacy, and speed of onset of efficacy, of pregabalin (PGB) and venlafaxine-XR (VXR) in patients with generalized anxiety disorder (GAD). In this double-blind trial, outpatients, ages 18–65 years, who met Diagnostic and Statistical Manual of Mental Disorders, 4th edition, criteria for GAD were randomized to 8 weeks of flexible-dose treatment with PGB (300–600 mg/day), VXR (75–225 mg/day), or placebo (PBO). The intent-to-treat sample consisted of 121 patients on PGB [least square (LS) mean±SE baseline Hamilton Anxiety Rating Scale (HAM-A), 27.6±0.4], 125 patients on VXR (baseline HAM-A, 27.4±0.4), and 128 patients on PBO (baseline HAM-A, 26.8±0.4). Treatment with PGB was associated with a significantly greater LS mean change in the HAM-A total score at last observation carried forward endpoint versus PBO (−14.5±0.9 vs. −11.7±0.9; P=0.028). Treatment with VXR was not significant versus PBO at endpoint (−12.0±0.9; −11.7±0.9; P=0.968). Treatment with PGB showed an early onset of improvement, with significantly greater LS mean change in the HAM-A by day 4 versus both PBO (−5.3±0.5 vs. −3.4±0.5; P=0.008) and VXR (−2.9±0.5; P=0.0012). The proportion of patients reporting a severe adverse event was similar for PGB (9.1%) and PBO (7.8%), but higher for VXR (20.0%; P<0.05). In conclusion, PGB was a safe and effective treatment of GAD, with a significantly earlier onset of anxiolytic activity than VXR.