Most individuals with generalized anxiety disorder (GAD) fail to achieve remission despite standard treatments. As a result, we examined the efficacy and tolerability of second-generation antipsychotics (SGAs) as (a) augmentation or (b) monotherapy for GAD. We searched MEDLINE, EMBASE, PsycINFO, the Cochrane Library, controlled trials databases, and the abstracts of scientific meetings for all trials of GAD treatment with SGAs in adults. Randomized, double-blind, parallel-group trials examining SGA augmentation and monotherapy were meta-analyzed. Five augmentation studies containing 912 adults with refractory GAD indicated that SGA augmentation was not more likely to produce clinical response or remission than placebo and was associated with an increased risk of all-cause discontinuation (relative risk [RR] = 1.43; 95% confidence interval [CI], 1.04-1.96). There was no difference in the Hamilton Anxiety Rating Scale on change from baseline or weight gain between groups. Four SGA monotherapy studies containing 1383 patients with GAD indicated that treatment with 150 mg of quetiapine was more likely to lead to a clinical response (RR = 1.31; 95% CI, 1.20-1.44), remission (RR = 1.44; 95% CI, 1.23-1.68), and a greater decrease in the Hamilton Anxiety Rating Scale score (-3.66; 95% CI, -5.13 to -2.19) than placebo. However, an increased risk of all-cause discontinuation (RR = 1.30; 95% CI, 1.09-1.54) and weight gain (2.2 lb; 95% CI, 1.16-3.24) was observed. Existing data suggest that SGAs are not superior to placebo as augmentation for refractory GAD. Quetiapine monotherapy is more efficacious than placebo for uncomplicated GAD, but issues with adverse effects and tolerability may limit its use.