The effect of various pharmacologic agents on lysis of L cells by guinea pig lymphotoxin (LT) was studied. Among the many drugs tested, only those that affect plasma membrane functions were found to interfere with the cytolytic action of LT. Dimethyl sulfoxide or lidocaine potentiated L cell resistance against lysis. Stronger protection was provided by ouabain. Addition of ouabain to cells previously injured by LT was also effective in reducing cell death. Attempts to detect metabolic disturbances in cells before LT cytolysis were unsuccessful. The biosynthetic rate of DNA, RNA, or protein, and the total cellular content of ATP were not significantly changed in LT-treated cells. The results suggest that LT disturbs some plasma membrane functions of the target cell, perhaps ion transport systems, and consequently induces ionic imbalances between the intra- and extracellular milieu which eventually cause cell death.