HIV-1 protease inhibitors (PIs) contribute to hyperlipidemia in persons treated for HIV infection. There are potential drug-drug interactions between PIs and some statins, which are drugs frequently used to treat hyperlipidemia. We performed a retrospective cohort study using the TennCare program to determine prescribing rates of contraindicated combinations of PIs and statins in HIV-infected persons in Tennessee and to assess changes in prescribing after publication of treatment guidelines. Computerized files identified adult patients with antiretroviral prescriptions and overlapping prescriptions for PIs and statins from January 1, 1996 through June 30, 2002. A subset of these combinations was defined as contraindicated based on published guidelines. Changes in patterns of prescribing after publication of preliminary treatment guidelines were examined using a mixed-effects logistic regression model. There were 3448 persons who received PIs during the study period. The proportion of PI users receiving statins increased from 3.5% during January 1996 through December 2000 to 7.9% during January 2001 through June 2002 (P < 0.001). Contraindicated PI-statin use decreased from 42.0% of combinations to 20.8% during the same periods (P < 0.001). Use of PIs and statins has increased in the adult TennCare population. Contraindicated combinations have decreased but remain unacceptably high.