As shown earlier for responsiveness to limiting doses of bovine serum albumin (BSA), strain 2 and not strain 13 guinea pigs form antibody when immunized with low doses of human serum albumin (HSA), an antigen strongly cross-reactive with BSA. (2 × 13)F1 animals responded as did the parental strain 2 animals, indicating dominant genetic control of responsiveness to limiting doses of BSA and HSA. Responsiveness to low doses of BSA in (2 × 13)F1 × 13 back-cross offspring was associated with inheritance of the PLL gene and also of the major strain 2 histocompatibility specificities. Genetic control of the immune response to BSA and HSA in strain 2 and strain 13 animals was specific, as no significant difference was observed in the antibody response of these guinea pigs to limiting doses of several other unrelated proteins. Random-bred Hartley guinea pigs immunized with low doses of HSA were distributed into distinct populations with high or low anti-HSA antibody responses. Responsiveness to limiting doses of HSA in these random-bred animals was not associated with possession of the PLL gene. Antihapten antibody response depended upon the gene controlling responsiveness to the carrier molecule in strain 2 and strain 13 guinea pigs immunized with limiting doses of DNP7-BSA. Strain 2 guinea pigs formed considerably higher levels of anti-DNP antibody than strain 13 guinea pigs in response to this antigen. In contrast, strain 13 guinea pigs developed significantly higher anti-DNP serum antibody levels than strain 2 animals when immunized with DNP6-GPA.