The relationship between the H-2 complex and the complement system was studied by performing functional assays for whole complement and individual complement components on sera from congenic mice of B10 and C3H backgrounds. Levels of whole complement activity were seen to be influenced by S region genes, confirming the work of others. Levels of C3 through C9, however, were independent of the H-I genotypes suggesting that the differences in whole complement activities were due to variation in levels of C1, C4 or C2. Titrations of these three earliest acting classical complement components were performed on sera from mice of nine strains of the B10 background and four strains of the C3H background. It was shown that functional levels of C1, C4, and C2 were all under control of genes within or very closely linked to the S region.