Comparisons of lymphocyte surface phenotypes and functions were made among 25 pediatric patients with congenital toxoplasmosis (ages 1 month to 5 years) and 24 uninfected babies, a baby with postnatally acquired infection, and 6 uninfected, 7 recently infected, and 6 chronically infected adults. Percentages of lymphocytes with B1, T11, T3, T4, T8, T6, B4, Ia, NKH phenotypes and T4 to T8 ratios of infected and uninfected babies were the same (p greater than 0.05). Lymphocytes from congenitally infected babies had lower blastogenic responses (mean stimulation index [SI] = 5) to Toxoplasma lysate antigens (TLA) than lymphocytes from adult control groups with recent and chronic infection (Mean SIs = 32, 72; p less than 0.001). Compared to infected adults, congenitally infected children had similar or greater responses to concanavalin A (mean SIs = 94; 118, 76, p greater than 0.05) and in mixed leukocyte culture (mean SIs = 63; 22, 26, p greater than 0.05). For symptomatic babies, low blastogenic response to TLA correlated with more severe disease at presentation (p = 0.002). Lymphocyte blastogenic responses to TLA were increased for most children when they were older than 15 months, but responses remained less than adult levels for 9 of the 17 older children studied. There was no correlation between concomitant serum pyrimethamine levels and lymphocyte blastogenic responses to TLA. Pyrimethamine and sulfonamide treatment in vitro and in vivo did not alter lymphocyte response to TLA. Lymphocytes from congenitally infected babies failed to produce either gamma interferon or Interleukin 2 when cultured with TLA. In contrast, they produced these lymphokines when cultured with concanavalin A or phytohemagglutinin. Specific deficits in cell-mediated immune responses to TLA may account for the significant organ damage that occurs in infants and children with congenital toxoplasmosis.