DNA probes containing the switch region (S) associated with the human immunoglobulin heavy chain mu gene were used to investigate polymorphisms in the germ-line human DNA. Six polymorphisms, detected by a single restriction enzyme (Sst I) are described. Linkage studies in 29 families show that five of the six polymorphisms, although relatively unassociated in random individuals, segregate in complete linkage one to the other and to Gm allotypes (markers on the heavy chain of IgG), while the sixth segregates independently. Altogether, when one considers the DNA markers at the five closely linked loci and the IgG1 and IgG3 heavy chain allotypes, 33 different haplotypes have been described; of these, 28 are detected by the DNA polymorphism alone. Study of 158-187 random haplotypes showed strong linkage disequilibrium only between one DNA polymorphism (Sst A) and Gm. Of the polymorphic Sst I loci, one, Sst E [associated with 2.2- to 2.7-kilobase (kb) fragments], is included in the mu chain S region (S mu); another, Sst A (6.8-7.4 kb), must be very close to the gamma 1-gamma 3 chain gene cluster. Based on studies of an IgE human myeloma, a third polymorphism, Sst C (4.8-5.5 kb), should map 3' of the active epsilon chain gene. An Sst I restriction enzyme map of phage clones carrying the two alpha chain genes indicates that Sst A and Sst C loci probably overlap with the alpha 1 and alpha 2 S regions, respectively. Both deletion/duplications and point mutations were detected.