Anaplastic large-cell lymphoma (ALCL) of T- or null-cell lineage, as defined in the revised European-American lymphoma classification, includes a subset of tumors that carry the t(2;5)(p23;q35) resulting in overexpression of anaplastic lymphoma kinase (ALK). Patients with ALK+ ALCL are reported to have a better prognosis than patients with ALK- ALCL. Because the mechanisms for this survival difference are unknown, we investigated the hypothesis that apoptotic pathways may be involved. We therefore assessed expression levels of the anti-apoptotic proteins BCL-2 and BCL-XL and the pro-apoptotic proteins BAX and BCL-XS in T/null-cell ALCL using immunohistochemical methods and correlated the findings with ALK expression and apoptotic rate (AR), the latter assessed by a modified Tdt-mediated dUTP nick-end labeling assay. ALK was detected in 21 of 66 (31.8%) ALCLs. BCL-2 was not detected in 21 ALK+ ALCLs but was present in 26 of 45 (57.8%) ALK- ALCLs (P < 0.0001). ALK+ and ALK- ALCLs also showed significant differences in expression of BCL-XL, BAX, and BCL-XS. ALK+ tumors less commonly had a high level of BCL-XL (1 of 17 versus 14 of 35, P = 0.01), and more commonly had high levels of BAX (13 of 18 versus 15 of 36, P = 0.05), and BCL-XS (11 of 16 versus 12 of 31, P = 0.05) compared with ALK- tumors. ALK+ tumors also had a higher mean AR than ALK- tumors (3.4% versus 1.1%, P = 0.0002). Differential expression of BCL-2 family proteins may be responsible for the higher AR observed in ALK+ ALCL and provides a possible biological explanation for the better prognosis reported for patients with ALK+ ALCL.