Landmark studies have proved that several therapies reduce cardiovascular disease (CVD) risk; however, the rates of secondary CVD in the context of therapies delivered according to current guidelines are largely unknown. Therefore, we sought to estimate the incidence of secondary CVD hospitalizations and all-cause mortality among patients who did and did not receive guideline-level pharmacotherapy. For the 12,278 patients added to the Kaiser Permanente, Northwest CVD registry in 2000 to 2005, we used the pharmacy records to define guideline-level care (GLC) as at least one dispense of aspirin/antiplatelets, statins, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and beta blockers within 6 months after registry enrollment. We followed patients until they died, experienced a CVD hospitalization, or June 30, 2008. We compared the age- and gender-adjusted incidence rates per 1,000 person-years of CVD hospitalization, death, and the composite, and estimated the hazard ratios using Cox regression analysis. During a mean follow-up of 45.8 +/- 22.8 months, 25% of the study sample experienced the composite outcome. The age- and gender-adjusted incidence per 1,000 person-years of the composite outcome was significantly lower among GLC patients (hazard ratio 50.3, 95% confidence interval [CI] 46.6 to 54.3) versus non-GLC patients (hazard ratio 60.7, 95% CI 58.1 to 63.4). The difference was driven by lower mortality rates (hazard ratio 18.1, 95% CI 16.1 to 20.4 vs hazard ratio 28.1, 95% CI 26.3 to 30.0). The incidence of CVD hospitalizations did not differ significantly between the 2 groups (hazard ratio 29.2, 95% CI 26.4 to 32.2 vs hazard ratio 27.7, 95% CI 26.0 to 29.5). Multivariate adjustment resulted in a marginally significant 8% lower risk of the composite outcome among GLC recipients (hazard ratio 0.92, 95% CI 0.83 to 1.01, p = 0.067). In conclusion, treatment according to current guidelines was significantly associated with reduced mortality but not the risk of secondary hospitalizations.