OBJECTIVES To compare dose-equivalence, adherence and subsequent switch rates among patients recently switched from a branded to generic version of the same statin (generic substitution, GS) vs. those switched from branded statin to generic version of a different statin (therapeutic substitution, TS). METHODS In a retrospective cohort analysis among adult enrollees in ~90 US health plans, we identified adult patients who switched from a branded to generic statin from July-December 2006. Patients were classified by type of statin switch: GS (eg, branded simvastatin °ú generic simvastatin), and TS (eg, branded atorvastatin °ú simvastatin). Demographic and clinical data were collected from claims before switch through six months follow-up. Outcomes of interest included proportion of patients that switched to a less potent daily dose, that switched back to the previous branded statin after switch, and that were at least 80% adherent during the 6 months after initial switch. Significant predictors of each clinical outcome were identified using multivariable logistic regression models, adjusting for differences between groups in covariates and potential confounders. RESULTS The TS (n=3,807) and GS (n=40,165) groups were generally similar demographically, although TS was more frequent in HMO health plans than GS (40.6% vs. 33.7%, p<.001), and less likely in POS plan patients (9.2% vs. 16.6%). Compared to GS, TS patients were more likely to be switched to a less potent dose (26.2 % vs. 0.5%); less likely to be adherent (70.2% vs. 79.5%); and more likely to switch back to the previous branded statin (11.3% vs. 2.9%, p<.001 for all). These effects remained significant in the regression models adjusting for demographic and baseline clinical characteristics. CONCLUSIONS TS is more likely to involve a subsequent disruption to statin therapy than GS. TS could potentially lead to adverse impacts on patients' outcomes, and should be studied further.