The genes encoding the two C4 isotypes, C4A and C4B, lie 10 kb apart in the class III region of the human major histocompatibility complex. The two isotypes exhibit extensive structural polymorphism. Characterisation of a number of C4A and C4B alleles has established the pattern of polymorphism in C4 and this has provided a structural basis for the observed functional and serological differences between the C4 isotypes. An intriguing feature in the genetics of C4 is the unusually high frequency of null alleles forming half null C4A and C4B haplotypes. Duplication of one of the loci has also been recognised. In addition the genes can differ in size due to the presence or absence of a large intron near the 5' end of the genes. These differences in gene size and gene number can be observed directly on different haplotypes using pulsed field gel electrophoresis.