BACKGROUND: Recent analyses have suggested an increased risk for serious asthma-related adverse events in patients receiving long-acting beta-agonists. PURPOSE: To examine whether the incidences of severe asthma-related events (hospitalizations, intubations, deaths, and severe exacerbations) differ in persons receiving salmeterol plus inhaled corticosteroids compared with inhaled corticosteroids alone. DATA SOURCES: The GlaxoSmithKline (Research Triangle Park, North Carolina) database, MEDLINE, EMBASE, CINAHL, and the Cochrane Database of Systemic Reviews (1982 to September 2007) were searched without language restriction. STUDY SELECTION: Randomized, controlled trials reported in any language that compared inhaled corticosteroids plus salmeterol (administered as fluticasone propionate/salmeterol by means of a single device or concomitant administration of inhaled corticosteroids and salmeterol) versus inhaled corticosteroids alone in participants with asthma. DATA EXTRACTION: Three physicians independently reviewed and adjudicated blinded case narratives on serious adverse events that were reported in the GlaxoSmithKline trials. DATA SYNTHESIS: Data from 66 GlaxoSmithKline trials involving a total of 20 966 participants with persistent asthma were summarized quantitatively. The summary risk difference for asthma-related hospitalizations from these trials was 0.0002 (95% CI, -0.0019 to 0.00231; P = 0.84) for participants receiving inhaled corticosteroids plus salmeterol (n = 35 events) versus those receiving inhaled corticosteroids alone (n = 34 events). One asthma-related intubation and 1 asthma-related death occurred among participants receiving inhaled corticosteroids with salmeterol; no such events occurred among participants receiving inhaled corticosteroids alone. A subset of 24 trials showed a decreased risk for severe asthma-related exacerbations for inhaled corticosteroids plus salmeterol versus inhaled corticosteroids alone (risk difference, -0.025 [CI, -0.036 to -0.014]; P <0.001). LIMITATIONS: The included trials involved selected patients who received careful follow-up. Only 26 trials were longer than 12 weeks. Few deaths and intubations limited the ability to measure risk for these outcomes. CONCLUSION: Salmeterol combined with inhaled corticosteroids decreases the risk for severe exacerbations, does not seem to alter the risk for asthma-related hospitalizations, and may not alter the risk for asthma-related deaths or intubations compared with inhaled corticosteroids alone.