At least 12 different C4 gene products with a three band pattern have been identified after electrophoresis of sera pretreated with neuraminidase. Segregation analysis showed at least 12 different C4 haplotypes (or supergenes), of which five represent a single gene product and seven are duplications each composed of an F and an S gene. The data analyzed with respect to linkage showed one recombinant between the C4 and HLAB loci in 154 meioses giving a map distance of C4 HLAB of 0.6 cM. Another recombinant between the C4 and the HLAD loci was found in 101 meioses giving a map distance of C4 HLAD of 1.0 cM. Linkage disequilibrium was found between at least eight C4 haplotypes and certain alleles at the HLAB as well as the HLAD loci. Examinations of 15 families selected through a proband with HLAA 25, HLAB 18 and C2Q0 showed that in almost all cases a slight variant of the C4 supergene F3S2 followed the haplotype HLAA25 HLAB18 C2Q0. No associations were found between the two duplications of C4F3 C4S2 and C4F3 C4S1 and the loci. These findings may indicate that these C4 haplotypes were the original ones preceding the other C4 haplotypes.