A dimorphic MspI RFLP (alleles M1 and M2) in an Alu unit 528 base pairs downstream from the apolipoprotein A-II gene on chromosome 1 was investigated for associations with dyslipoproteinaemia or coronary atherosclerosis. No significant differences were observed between the allele frequencies in healthy random controls (M2 = 0.850, n = 70) and patients with primary hypertriglyceridaemia (M2 = 0.846, n = 52) or severe coronary atherosclerosis (M2 = 0.819, n = 47). The apolipoprotein A-II gene may also contribute to the regulation of plasma levels or composition of HDL in response to environmental changes. To study the effect upon apolipoprotein A-II variability, 42 monozygotic twin pairs were genotyped for the MspI RFLP. Pairs with the genotype M2M2 (n = 28) had significantly smaller within-pair differences in plasma apolipoprotein A-II levels (2.2 vs 5.8 mg/dl, P < 0.02; Mann-Whitney) than those with other genotypes (n = 14). The M2 allele may be in linkage disequilibrium with a functional mutation that restricts the variability of plasma apolipoprotein A-II in response to environmental conditions. This provides a new example of a 'variability' gene, one of an important group of loci which may alter responses to hypolipidaemic therapy and cardiovascular risk.