This paper examined the interaction between genetic influences of the polymorphic human leukocyte antigens (DRB1 and DQB1) and psychological distress on the development of cellular immunity to the novel antigen, keyhole limpet hemocyanin (KLH). Participants (n = 227) were immunized with KLH and the development of cutaneous delayed-type hypersensitivity (DTH) against KLH was examined 3 weeks later. Distress was assessed using the Profile of Mood States. DNA was typed for the serologically defined DRB1 and DQB1 antigens. There was a significant correlation between distress at immunization and the development of DTH skin test responses to KLH (n = 214, r = .24, p = .003). HLA DQ2 was weakly associated with a decreased likelihood of developing a cutaneous delayed-type hypersensitivity response against KLH (odds ratio [OR] = 1.6; confidence interval [CI] 0.9-2.7). HLA DQ5 was weakly associated with an increased likelihood of responding to the antigen (OR=0.6; CI=0.3-1.0). The correlation between distress and immune function in HLA DQ2 negative individuals was .34 (n = 136, p = .00) and in HLA DQ2 positive individuals it was .06 (n = 74, p =. 64). For HLA DQ5 negative individuals the correlation was .26 (n = 140, p = .00) and for HLA DQ5 positive individuals it was .22 (n = 70, p = .07). These results suggest that the distress/immune relationship in genetically susceptible or protected individuals may be underestimated in psychoneuroimmunology research.