A systematic review and meta-analysis were conducted to evaluate the comparative efficacy and tolerability of second-generation antidepressants in social anxiety disorder. Studies were identified by searching MEDLINE, Embase, The Cochrane Library, PsychLit, and the International Pharmaceutical Abstracts from January 1980 through October 2006. Comparative evidence was summarized and indirect comparisons were made using network meta-analysis. Only three head-to-head trials were identified; comparative trials found only minimal differences in efficacy between escitalopram and paroxetine, and no statistically significant differences in efficacy between extended-release venlafaxine and paroxetine. Pooled evidence from 15 placebo-controlled trials suggests that escitalopram [relative benefit (RB) 1.3; 95% confidence interval (CI) 1.2–1.5], paroxetine (RB 1.9; 95% CI 1.5–2.3), sertraline (RB 1.8; 95% CI 1.5–2.2), and venlafaxine (RB 1.7; 95% CI 1.5–1.9) all produce significantly more responders than placebo; evidence favored fluvoxamine over placebo but was not significant (RB 1.5; 95% CI 0.9–2.4). Network meta-analysis did not reveal differences in efficacy among drugs. Overall, a fair amount of evidence supports the efficacy of escitalopram, fluvoxamine, paroxetine, sertraline, and venlafaxine in social anxiety disorder. The drugs do not differ in efficacy, although their adverse event profiles do.