Fludarabine has emerged as salvage therapy in chlorambucil-resistant CLL. However, encouraging response rates have been compromised by a high incidence of serious infectious complications. Prophylactic measures to reduce the frequency of infections are needed, but up to now, there are no established standards for supportive therapy in fludarabine-treated CLL. Clinicians have observed an increasing frequency of life-threatening opportunistic infections but only some of these may be explained by fludarabine-induced impairment of cell-mediated immunity. Neutrocytopenia commonly found during initial fludarabine treatment may not have been addressed sufficiently as risk factor for infections. Thus, G-CSF supplementation may improve the rate of infectious complications by reducing the duration of fludarabine-induced neutrocytopenia. The changing spectrum of infectious complications should stimulate additional trials on the value of IVIG replacement in fludarabine-treated CLL patients and on the role of low-dose co-trimoxazole in patients at high risk of Pneumocystis carinii infections.