Evidence is presented that the percentage and number of some subsets of T and B cells in normal children and adults vary greatly from those in fetal life and throughout the first few years after birth, and less so during adolescence and adulthood. Depending then on the age at which immunological studies are performed, as well as whether the HIV infection occurs in utero, at birth, or postnatally, values obtained by immunophenotypic analyses of differentiating or mature immunocytes will vary greatly. A concerted effort needs to be made to measure different developmental and activation immunophenotypic markers, from birth on, in premature and full-term infants of varying socioeconomic and ethnic background. Results from such studies should improve our ability to determine the timing of HIV infection, to obtain earlier guidelines for prophylaxis or treatment of the virus or of opportunistic infections, as well as to improve prognostic capabilities in perinatal HIV infection.