The previous paper suggested that the primary action of guinea pig lymphotoxin (LT) involved creation of ionic imbalances within the target [mouse fibroblast] L cells. The nature of these ionic disturbances is explored in this paper. The exogenous addition of CaCl2, but not KCl or NaCl, inhibited the cytotoxic action of LT. Cellular uptake rates of 45 Ca++, but not 86Rb+, increased in LT-damaged L cells. The factor responsible for increasing the 45Ca++ uptake rate cochromatographed on a hydroxyapatite column with the cytotoxic activity of LT. Ouabain prevented the LT-mediated lysis and, concomitantly, depressed the LT-induced increase of 45Ca++ uptake rate. The LT-damaged L cells excluded trypan blue to the same extent as the normal cells. The addition of LT to an LT-resistant L cell mutant affected neither the 45Ca++ uptake rate nor the viability. Damage to the Ca transport system in the L cell plasma membrane is proposed as a mechanism of LT action.