Human parainfluenza virus type 3 (HPIV3) is a major cause of disease in newborns and infants. It also has a striking potential to reinfect individuals throughout their lives, suggesting that HPIV3 does not induce lifelong immunity; however, the operative mechanism for the failure to prevent reinfection is not known. We have assessed the potential of the virus to infect nontransformed human T lymphocytes and have found that T cells are readily infected by the virus. Productive infection requires activation of the T cells and results in a marked inhibition of proliferation. Furthermore, our results indicate that exposure to the virus, even without overt expression of viral proteins as detected by immunohistology, profoundly alters the functional capacity of the T cells. The capacity of the virus to regulate T-lymphocyte function may play an important role in the failure of the virus to induce lifelong immunity.