In this report we studied a 35-year-old male who developed an abnormal expansion of granular lymphocytes (GL) which spontaneously regressed over a period of 2 years. The immunological and molecular characterizations of expanded cells showed the CD3+,CD8+,HNK-1+ phenotype, a polyclonal organization of the T-cell receptor beta-chain gene and normal natural killer activity. At the time of presentation, spot and blot hybridization techniques revealed the presence of viral hepatitis B virus (HBV) DNA sequences only in highly enriched CD4+ T cells, while proliferating GL were negative. With this as a background, we addressed the question of whether in our case the polyclonal GL proliferation represented an immunoreactive response against CD4+ infected cells. In particular, we tested the possibility that expanded GL could be cytotoxic against autologous infected CD4+ cells. At the time of the first determination, when several of the CD4+ cells harbored HBV, GL showed a minimal degree of cytotoxicity against 51Cr-labeled CD4+ cells; 2 years later, when GL became capable of lysing these targets, the appearance of the specific cytotoxicity was concomitant with the disappearance of the HBV-infected CD4+ cells and with the recovery of granular lymphocytosis. Taken together, our data suggest that in this case GL proliferation could represent an immunoreactive process against CD4+ cells.