Familial combined hyperlipidaemia (FCHL) is one of the most common hereditary disorders predisposing to early coronary death. The affected family members have elevations of serum total cholesterol, triglycerides or both. Despite intensive research efforts the genetic and metabolic defects underlying this complex disorder are still unknown. To dissect the metabolism and genetics of FCHL the phenotype of an individual must be precisely defined. We assessed the influence of different diagnostic criteria on the phenotype definition and studied factors affecting the phenotype expression in 16 large Finnish families (n = 255) with FCHL. The fractile cut-points used to define abnormal lipid values had a profound influence on the diagnosis of FCHL. If the 90th percentile cut-point was used, approximately 45% of the family members were affected, in concord with the presumed dominant mode of transmission for FCHL. If the 95th percentile was used only 22% of study subjects were affected. To characterize the metabolic differences or similarities between the different lipid phenotypes, we determined very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), low density lipoprotein (LDL) and high density lipoprotein (HDL) particles separated by ultracentrifugation. In linkage analysis no single ultracentrifugation variable could discriminate reliably affected family members from non-affected family members. Our data emphasizes the need for re-evaluation of FCHL diagnostic criteria. Preferably, the diagnosis should be based on a single, reliable metabolic marker.