Although chronic lymphocytic leukemia (CLL) remains an incurable disease with standard chemotherapy, the appropriate role and timing of transplantation are unclear. In this analysis, we report the outcomes of 46 patients with advanced CLL who underwent nonmyeloablative stem cell transplantation (NST) from HLA-matched unrelated (67%) or related (33%) donors. Fludarabine (30 mg/m2 x 4) and low-dose intravenous busulfan (0.8 mg/kg/day x 4) were used for conditioning. The 2-year overall survival (OS) and progression-free survival (PFS) rates in this refractory patient population were 54% and 34%, respectively, with a median follow-up of 20 months. The primary cause of treatment failure was relapse, with a 2-year cumulative incidence of 48%. High hematopoietic donor chimerism > or = 75% at day +30 was a significant predictor of 2-year PFS (47% vs 11%; P = .03). In multivariate analysis, chemotherapy-refractory disease at transplantation was associated with a 3.2-fold risk of progression (P = .01) and a 4.6-fold risk of death (P = .02). Increasing number of previous therapies and increasing bone marrow involvement were also associated with decreased PFS and OS. These results suggest that NST using fludarabine and low-dose intravenous busulfan is a reasonable treatment option for patients with advanced CLL, but that NST earlier in the disease course will likely be needed to achieve long-term disease control in a high proportion of patients.