CD38 is an approximately 45-kDa type II transmembrane glycoprotein expressed by hematopoietic and nonhematopoietic cells. Its surface expression is under complex control and varies during lymphocyte development, activation, and differentiation, suggesting an important role in these processes. Murine CD38 has been mainly characterized on B lymphocytes, and in humans, the molecule has been studied in T cells. This paper provides evidences that murine CD38 is regulated tightly during T cell activation and differentiation. On the periphery, a subset of mature T lymphocytes was identified by the expression of CD38. These cells showed an activated phenotype; they were larger and more granular than their negative counterparts. In accord with this observation, in vitro-activated T cells up-regulated CD38. Memory T lymphocytes also were CD38-positive. It is interesting that T cells expressing high levels of CD38 had a reduced, proliferative capacity but displayed an improved potential to produce interleukin-2 and interferon-gamma, suggesting a role of this molecule during T cell activation and differentiation.