Several reports have shown that HLA-B8,DR3 positive subjects may display some changes in immune parameters when compared with HLA-B8,DR3 negative ones and are prone to develop several immunological diseases. In the present study we have analysed the proliferative response to phytohaemagglutin (PHA) in HLA-typed healthy subjects. A twin method was also employed to assess the role of genetic and environmental factors in the regulation of the response to the mitogen. It was not possible to demonstrate any difference in proliferative response to optimal doses of PHA between groups of subjects carrying or not carrying the HLA-B8,DR3 phenotype. When suboptimal responses were studied, however, the results showed that lymphocyte responses were significantly decreased in HLA-B8,DR3 positive subjects compared with the negative ones. Moreover, the experiments performed with twins demonstrated that environmental factors were more important than genetic factors in the proliferative response to mitogen. The fact that the HLA-B8,DR3 phenotype affects the suboptimal response to PHA although environmental factors are more important than genetic factors in the response to the mitogen seems of some interest. However, these results could be consistent with the high incidence of autoimmune disorders among HLA-B8,DR3 positive individuals.