Natural-killer(NK) activity was examined in the presence of low oxygen tension, low glucose concentration and acidic pH, to determine whether physical conditions present in the tumor micro-environment could play a role in down-regulating cytolytic activity of tumor-infiltrating lymphocytes with NK phenotype. Anoxia (0% O2), but not hypoxia (1% O2), significantly reduced NK activity, as did acidic pH (6.4 or 6.7). Low glucose concentration (6 mg/dl) did not impair NK activity. Combinations of either moderate (1% O2, 26 mg/dl glucose, pH 6.7) or extreme (0% O2, 6 mg/dl glucose, pH 6.4) alteration of physical conditions significantly reduced NK activity. This study indicates that the physico-chemical conditions present within solid tumors are capable of down-regulating NK activity.