OBJECTIVES Aspirin may interact with ACE inhibitors to reduce their beneficial effects in patients with heart failure. The objective of this retrospective cohort study was to assess the risk of congestive heart failure (CHF) hospitalization in patients with heart failure (HF) taking ACE inhibitors in a large national cohort of veterans. METHODS Exposure to aspirin was assessed between October 1, 2000 and September 30, 2001. Patients were characterized as prescribed: no aspirin, low-dose (≤ 81 mg) aspirin, high-dose (>81 mg) aspirin. Time to HF hospitalization in these selected patients was assessed between October 1, 2001 and September 30, 2002. Chi-square tests, Kaplan-Meier plots and log-rank tests were employed for testing bivariate associations. A multivariable Cox regression model was used to estimate the adjusted hazard ratio for the risk of CHF hospitalization due to aspirin exposure after controlling for sociodemographic factors, comorbidities, comedications, and years with HF. RESULTS The final study cohort consisted of 157,088 HF patients with a mean age of 69.75 (± 10.19) years. The crude HF hospitalization rates differed significantly between the treatment groups (log-rank statistic for KM plot: p-value <0.001). In multivariate analysis of the association of aspirin use and hospitalization for CHF the use of both high-dose aspirin (HR 1.26, 95% CI 1.19-1.34) and low-dose aspirin (HR 1.18, 95% CI 1.09-1.27) was associated with increased risk of CHF hospitalization with no aspirin use as the reference group. The results remained the same for high-dose aspirin in case of patients: with both CHF and IHD, without IHD, age<65 years, age ≥ 65 years and patients with Medication Possession Ratio (MPR) ≥ 0.8. CONCLUSIONS The theory of negative interaction between ACE inhibitors and aspirin may be true, but results must be interpreted with caution. Prospective studies would be needed to investigate this interaction further.