The S region of H-2 controls a polymorphism of the gamma-chain of C4 (gamma 1, gamma 2, and gamma 3) as shown by differences in their isoelectric points. The G region of H-2 was defined by the presence of an alloantigen (H-2.7) on erythrocytes and serum. We found that antisera to H-2.7 immunoprecipitated C4 and no other protein from mouse EDTA-plasma. Furthermore, all H-2.7-positive strains bear C4-gamma 1, and conversely, H-2.7-negative mice bear C4-gamma 2 or gamma 3 (with one exception; see below). The H-2.7 specificity resides on C4d, a 45,000-mol wt fragment generated from the cleavage of the alpha'-chain of C4b by serum control proteins. Because the C4d fragment bears the labile binding site of C4 for cell membranes, it is likely that the erythrocyte alloantigen is acquired from serum as a result of the activation of C4. On the basis of these findings, the existence of a separate G locus is unlikely. Our results also show that C4-gamma 1 and C4-gamma 2 differ from each other at least in their alpha- and gamma-chains, and may represent complex allotypes. No trans effects were observed in F1 hybrids between H-2.7-positive and -negative mice. Mice that bear the k allele in the S region are exceptional in two respects: they are C4-deficient and their C4 molecules bear gamma 2 chains and the H-2.7 alloantigen. Perhaps the low levels of C4 are a consequence of the genetic event leading to this unusual alpha-gamma-chain combination.