During hematopoiesis, viability factors that suppress apoptosis are required throughout the differentiation process. Some of these factors may also function as growth factors. Interleukin-5 (IL-5) is recognized as a growth factor in hematopoiesis. We examined the involvement of IL- 5 as a viability factor of B-CLL in vitro. In 13 B-CLL cases studied, IL-5 at 20 U/mL increased spontaneous apoptosis by a mean percentage of 53% (range, 20% to 129%) (P < .05) after 2 days in culture. On the third day, the mean percentage increase was 37% (range, 18% to 50%). In all cases, IL-4 protected B-CLL cells against IL-5-induced apoptosis by a mean percentage of 47% (range, 18% to 81%) (P < .001). This protection was specific to IL-4 and it was reduced with anti-IL-4 antibody. In addition, expression of bcl-2 protein in untreated cultures was not significantly different from that of the IL-5-treated cells; mean equivalent of soluble fluorochrome (MESF) was 5.2 (range, 3.0 to 6.8) and 4.9 (range, 3.0 to 6.3), respectively (P > .2). In freshly isolated B-CLL cells, the MESF was 4.5 (range, 2.4 to 6.6). These results show that IL-5 induced apoptosis in B-CLL cells by a pathway that is independent of bcl-2 expression. IL-4 partially protects against this effect.