L2C leukemia is a leukemia that occurs in strain two guinea pigs. The L2C cells are natural killer-sensitive. The Kurloff cell (KC), a guinea pig NK cell, develops a 3-fold increase in lysosomal enzyme activity and the number of KC cells increases during leukemogenesis, leading to KC cell-mediated L2C cytolysis. This paper shows that conjugates are produced by incubating KC and L2C for 4 h, with 34% of L2C showing chromatin compaction and shrinkage of the cytoplasm. There was also a reorientation of the KC cytoplasmic organelles to face the target cell and an elongation of the KC to produce arms that engulfed the L2C. The L2C had either necrotic or apoptotic characteristics. L2C DNA fragmentation was demonstrated in situ with the comet and the TUNEL assays. 22.2% of the viable L2C lost their membrane asymmetry during KC-L2C conjugation as shown by incubation with Annexin V-FITC. These results provide new evidence that the death of L2C is due, at least partly, to apoptosis. The cytolytic effect of the NKKC might be a model of the cytological changes that occur in NK cell-leukemic cell conjugates.