Many patients with severe primary hypercholesterolemia—lowdensity lipoprotein cholesterol (LDL-C) >240 mg/dL—have heterozygous familial hypercholesterolemia. In such familial hypercholesterolemic patients, the lipid-lowering efficacy of fluvastatin is related to genetic factors, and it is of interest whether the response to treatment differs from that in patients with more moderate hypercholesterolemia. Thus an exploratory analysis of randomized, controlled clinical trials and their open-label extensions (12–78 weeks), conducted worldwide with fluvastatin ≥20 mg/day (n = 1810) and placebo (n = 783), assessed whether, apart from the potential differences between familial hypercholesterolemic and nonfamilial hypercholesterolemic patients, the response to 40 mg of fluvastatin is influenced by baseline plasma lipid levels in relation to disease severity. Entry criteria included LDL-C ≥190 mg/dL with ≤1 risk factor and no coronary artery disease, or ≥160 mg/dL with >1 risk factor or definite coronary artery disease. Of these patients, 591 (33%) given fluvastatin (20–40 mg/day) and 187 (24%) given placebo had severe hypercholesterolemia with baseline LDL-C >240 mg/dL. In controlled studies, the mean ± SD duration of exposure was 21.1 ± 16.1 and 19.4 ± 15.5 weeks for fluvastatin and placebo, respectively, whereas longterm efficacy was assessed after 55.3 ± 21.7 weeks (fluvastatin) and 21.1 ± 12.3 weeks (fluvastatin + cholestyramine, after previous monotherapy). In summary, fluvastatin at 40 mg/day lowered LDL-C by 25–26% from baseline in controlled studies (n = 622), and by 27% in long-term studies (32–33% with fluvastatin + cholestyromine; n = 386), irrespective of severity of cholesterolemia. High density lipoprotein cholesterol (HDL-C) and triglyceride responses were enhanced, when at baseline HDL-C levels were low and triglycerides raised, irrespective of baseline cholesterolemia, whereas the LDL-C response was unrelated to baseline in patients with LDL-C levels >240 mg/dL. In patients in the highest triglyceride tertile, fluvastatin plus cholestyramine apparently abolished the triglyceride increase expected with cholestyromine. This influence of baseline levels on fluvastatin response can be considered beneficial, as hypercholesterolemic patients with low HDL-C and high triglyceride levels are at particularly high cardiovascular risk.