Guinea pig lymphotoxin inhibits the growth of mouse alpha L929 and guinea pig 104C1 tumor cells with lethal doses (LD 50's) of 0.4 and 200 units lymphotoxin/ml, respectively, in a colony inhibition assay. Refeeding with lymphotoxin-free medium is followed by resumption of 104C1 but not alpha L929 cell growth. This suggests that growth inhibition of alpha L929 is primarily due to cytolytic mechanisms, while that of 104C1 cells is due to cytostatic mechanisms. This is confirmed by radionuclide (3H, 51Cr, and 75Se) release assays with LD 50's of 1.0, 1.9, and 2.4 units lymphotoxin/ml, respectively, for alpha L929 cells, whereas as many as 100 units lymphotoxin/ml produce no radionuclide release from 104C1 cells. The L cell variant L929M is 10-fold more resistant to lymphotoxin colony inhibitory activity and 40-300-fold more resistant to cytolytic lymphotoxin activity as measured by the three radionuclide release assays than are alpha L929 cells. L929 and 2071 L cell variants are more resistant as a result of smaller cytolytic and cytostatic responses and some tumor cells, such as one strain of L1210 mouse leukemia cells, exhibit no detectable cytolytic or cytostatic responses to 100 units of guinea pig lymphotoxin. These observations demonstrate that the divergent susceptibilities of different cells to lymphotoxin result in part from constitutive variations in cellular cytolytic and reversible cytostatic responses to lymphotoxin.