The genetic regulation of immune responsiveness by genes from two independent, highly polymorphic genetic systems, namely immunoglobulin allotypes and human leukocyte antigens (HLA), was studied in 35 healthy Caucasian volunteers. The in vivo IgG class antibody response to the primary test immunogen alpha-helix pomatia hemocyanin (HPH) was increased in subjects with the Gm1,17;..;21 haplotype compared to that of the non-Gm1,17;..;21 group. The IgM-class response tended to be higher in the former group. Levels of in vivo IgA-class-specific anti-HPH antibodies tended to be higher in the group of individuals positive for HLA-B8/DR3 than in the non-B8/DR3 group. This difference was statistically significant only in the absence of the Gm1,17;..;21 haplotype. The in vitro lymphocyte proliferative response on mitogenic stimulation with phytohemagglutinin (1 micrograms/ml) and pokeweed mitogen (10 micrograms/ml) also appeared to be associated with both systems. The presence of the Gm1,17;..;21 haplotype was associated with decreased lymphocyte reactivity, whereas the B8/DR3 phenotype was associated with high responsiveness to these mitogens. However, in the presence of the Gm1,17;..;21 haplotype subjects positive for HLA-B8/DR3 did not respond better to mitogenic stimulation than those lacking this HLA haplotype. Our results imply that the immunogenetic make-up of test persons should be taken into account in the assessment of the immune status of individuals or groups of patients.