Background Recent reports suggest an association between beta-agonists and the risk of incident chronic heart failure (CHF). We sought to examine the association between inhaled beta-agonists and risk,of incident and nonincident heart failure. Methods We performed a nested case-control study within the Ambulatory Care Quality Improvement Project (ACQUIP). Case subjects were defined as having had a hospitalization with a primary discharge diagnosis of CHF. Controls were randomly selected from the ACQUIP cohort. The exposure was the number of beta-agonist canisters filled in the 90 days before an index date. Results After adjusting for potentially confounding factors, there appeared to be no association between the use of inhaled beta-agonists and the risk of heart failure (1-2 canisters per month, OR 1.3 [95% Cl 0.9, 1.8], greater than or equal to3 canisters per month, 1.1 [95% Cl 0.8, 1.6]). However, among the cohort that had a history of CHF, there appeared to be a close-response association between the number of inhaled beta-agonists and the risk of hospitalization for chronic heart failure (1-2 canisters per month, adjusted OR 1.8 [95% Cl 1.1, 3.0], greater than or equal to3 canisters per month, adjusted OR 2.1 [95% Cl 1.2, 3.8]). Conclusion beta-Agonists did not appear to be associated with incident heart failure but were associated with risk of CHIF hospitalization among those subjects with a previous CHIF diagnosis. Although a causal relationship cannot be inferred from these findings, further research is warranted to determine the safety and effectiveness of inhaled beta-agonists for patients with CHF.