BACKGROUND: Cardiovascular risk might be reduced by targeted changes in both low density and high density lipoprotein cholesterol (LDL-C and HDL-C). This dual strategy will require a well tolerated, effective regimen, as well as a better understanding of how HDL-C may be targeted. DESIGN: An open-label, uncontrolled, retrospective cohort study of combined statin-niacin therapy. METHODS: We reviewed all patients ( n= 132) started on this combination in a referral lipid clinic over a 6.5-year period for tolerability, safety and effectiveness. RESULTS: Combined therapy was tolerated by 77% of patients. No serious adverse events attributable to medication were encountered. In drug-naive patients (n = 37), moderate doses of statin and niacin (mean 1180 mg/day) reduced LDL-C 31% and increased HDL-C 29% ( P< 0.002, both comparisons). At niacin doses >or= 1000 mg/day (mean 1480) added to a constant statin regimen (n=29), HDL-C increased 20% ( P< 0.001). Even at niacin doses < 1000 mg/day (mean 580, n= 23), HDL-C increased 13% ( P< 0.05). Although mean HDL-C increased, the initial and final HDL-C distributions were broad and largely overlapping. Any chosen cutpoint for HDL-C goal would apply to only a minority of patients. The total/HDL cholesterol ratio had narrower distributions, as the percentage of patients with ratio < 5.0 increased from 17% to 67%. CONCLUSION: Combined statin-niacin therapy lowers LDL-C and raises HDL-C with acceptable tolerance and safety. If treating LDL-C is the primary goal, consistent with current guidelines, then a strategy of targeting the total/HDL cholesterol ratio as a secondary goal is applicable to more patients than targeting HDL-C itself.