OBJECTIVE In order to assess the long-term (12 months) efficacy and safety of fenofibrate administered with simvastatin in the treatment of primary mixed hyperlipidaemia, we conducted a study that compared increasing dosages of these drugs in subgroups of men and women belonging to a clinical sample of out-patients. METHODS This was an open study carried out in patients with primary mixed hyperlipidaemia (lipoprotein phenotype IIb) who needed a combined therapeutic approach because of their poor response to a single-drug regimen with an HMG-CoA reductase inhibitor (simvastatin). Thus, a fibrate (fenofibrate) was added to the therapy. The study lasted 12 months. METHODS Forty-five patients (mean age: 58.9 +/- 11.3 years) with primary mixed hyperlipidaemia who showed a poor response to the single-drug hypolipidaemic treatment were enrolled. Their average plasma triglyceride level was consistently above 300 mg/dL and low-density lipoprotein cholesterol (LDL-C) was over 160 mg/dL after at least 6 months of a single hypolipidaemic drug (simvastatin) regimen plus antiatherogenic dietary treatment. METHODS Five patients received simvastatin 10mg once daily in addition to fenofibrate 200mg; 26 patients received simvastatin 20mg once daily plus fenofibrate 200mg; 11 patients received simvastatin 20mg once daily plus fenofibrate 300mg; and three patients received simvastatin 30mg once daily plus fenofibrate 200mg. The patients were allocated to treatment groups on the basis of their relative response to the therapy. Those making up the progressively higher agent/dose groups were the individuals at higher cardiovascular risk according to the total cholesterol and non-high-density lipoprotein cholesterol (HDL-C) values. RESULTS The double-drug regimen given for 12 months to four different groups, according to the different combined dosages of simvastatin and fenofibrate, resulted in a reduction in total cholesterol of 18% (p </= 0.05) to 39% (p </= 0.05), in LDL-C of 21% (not significant) to 39% (p </= 0.05) and in triglycerides of 35% (p </= 0.05) to 56% (p </= 0.01), and an increase in HDL-C of 8% (p </= 0.05) to 30% (not significant). The cardiovascular risk ratio (total cholesterol/HDL-C) at the end of the study was reduced by 33-60%, whereas the non-HDL-C decreased by 25-38%. No serious adverse effects were reported by the patients. Neither liver biochemistry nor creatine kinase serum concentration were significantly changed. Discontinuation of treatment, if necessary, in case of the occurrence of clinically subjective or objective evidence of adverse effects was assured. CONCLUSIONS The results confirmed the efficacy of the combination of fenofibrate and simvastatin. The combined therapeutic approach was shown to be safe for the treatment of primary mixed hyperlipidaemia, at least in patients with normal hepatic and renal function.