Rituximab has been associated with the development of late-onset neutropenia (LON). As only heterogeneous studies have been conducted, its incidence and clinical course remain unclear. We aim to: (1) study the incidence and clinical relevance of WHO grade 3/4 LON in a uniform group of patients with diffuse large B-cell lymphoma (DLBCL) in complete remission following curative rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (RCHOP) chemotherapy; (2) ascertain predictive factors for LON. The 121 eligible patients identified from our prospectively maintained database were followed up for occurrence of WHO grade 3/4 LON. The clinical course of LON was documented, and its relationship with patient- and tumor-related factors was analyzed. With a median follow-up of 883 days (range, 265-1762), 13.2% had developed LON of grade 3/4. The median time to neutrophil nadir was 129 days (range, 39-277). The median time to recovery was 69 days (range, 3-349) and occurred in all except two patients. Only one episode of nonlife threatening bacterial culture-positive urinary tract infection and pulmonary tuberculosis, both occurring in the same patient was documented. Results of Fischer's exact test revealed that age, stage, LDH level, ECOG, marrow involvement, and hematologic parameters did not predict for LON development. WHO grade 3/4 LON is not infrequent in patients with DLBCL receiving RCHOP. Even so, it is reassuring that LON is self-limiting and unassociated with life-threatening infection. A watchful waiting approach is appropriate in majority of patients who develop LON following RCHOP. Am. J. Hematol., 2009. (c) 2009 Wiley-Liss, Inc.