Adding long-acting beta agonists (LABA) to inhaled corticosteroids (ICS) has been associated with beneficial effects in COPD patients in randomized controlled trials and observational studies. However, it is not known whether adding short-acting beta agonists (SABA) to ICS instead of LABA will be similarly effective in COPD. We compared the effectiveness of combination therapies involving ICS with LABA versus ICS with SABA in reducing risk of re-hospitalization or death among COPD patients within a year of discharge from a first COPD hospitalization. Using the UK General Practice Research Database, we obtained 437 pairs of patients who either used ICS plus LABA or ICS plus SABA, each pair having been matched on disease severity. We found that 12.1% of patients prescribed ICS with LABA experienced re-hospitalization or death within 12 months compared with 18.1% among those given ICS with SABA. In multivariate analyses, we found a 38% risk reduction (P<0.007) among patients given ICS with LABA relative to those given ICS with SABA. Models stratified by SABA use generated a risk reduction of 35% (P=0.02) among those given ICS and LABA with SABA in the 90-day period, and of 49% (P<0.05) among those given ICS and LABA without any SABA compared with the combination users of ICS and SABA. We conclude that in moderate to severe COPD patients, the combined use of ICS with LABA is more effective in reducing the risk of re-hospitalization or death than the combined use of ICS with SABA.