Reducing low-density lipoprotein (LDL) cholesterol with statins reduces cardiovascular risk, but the associations between increases in high-density lipoprotein (HDL) cholesterol and cardiovascular risk at different LDL levels have been less well characterized. To evaluate the associations between the 1-year changes in HDL cholesterol and LDL cholesterol with lovastatin and subsequent acute major coronary events (AMCEs), we studied 2,928 patients in the lovastatin arm who were followed for 5.2 years in a post-hoc analysis of the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). The percentage of HDL cholesterol increase and apolipoproteins at year 1 and the incidence of AMCEs thereafter were assessed stratified by the LDL cholesterol levels. With lovastatin, LDL cholesterol was reduced by 25% on average to 115 mg/dl at year 1, and HDL cholesterol increased 6.0%. Patients with both an increase in HDL cholesterol of > or =7.5% and LDL cholesterol of <115 mg/dl at year 1 had the lowest event rate (3.53/1,000 person-years; p = 0.028). Similar results were found for an increase in HDL cholesterol of > or =7.5% and a decrease in LDL cholesterol of >25%, as well as for apolipoproteins A-I and B. The 1-year percent increase in HDL cholesterol appeared to be associated with a reduction in AMCEs in subsequent follow-up (p = 0.07 with the percentage of HDL cholesterol increase analyzed continuously). Patients with an HDL cholesterol increase of > or =7.5% had an AMCE rate of 5.18 compared with 7.66/1,000 person-years in patients with a lower HDL cholesterol increase (p = 0.08). In conclusion, lovastatin therapy was associated with a greater risk reduction of AMCEs when LDL cholesterol was substantially reduced and the HDL cholesterol increased by > or =7.5%.