A longitudinal analysis of natural killer (NK) cell-mediated cytotoxicity of maternal peripheral blood lymphocytes was carried out at various stages (16-36 weeks) of normal human pregnancy, within 1 week following delivery and up to 40 weeks post-partum. NK cell-mediated lysis of K562 target cells (TC) in short term 51Cr-release assays was significantly depressed throughout pregnancy, returning to control levels 9-40 weeks post-partum. Natural cytotoxicity of unseparated maternal peripheral blood was also substantially depressed at all stages of pregnancy and, in addition, remained impaired in the late post-partum period. Longitudinal enumeration of Leu 3a+ and Leu 2a+ lymphocytes indicated an absence of helper/suppressor T-cell imbalance during pregnancy, and analysis of Leu 7+ cells showed no difference in population sizes between control and pregnancy groups. Comparison of blood and lymphocyte cytotoxicity in control and pregnancy samples suggested a complex regulation of NK reactivity during pregnancy. The potential role in vivo of both plasma-associated and cellular regulatory elements is discussed.