Background Secondary cytopenias are serious complications following hematopoietic cell transplantation. Etiologies include myelotoxic agents, viral infections, and possibly transplant-related factors such as the intensity of the conditioning regimen and the source of stem cells. Design and Methods We retrospectively analyzed data from 2162 hematopoietic cell transplant recipients to examine the effect of these factors on overall cytopenias occurring after 28 days in hematopoietic cell transplantation. Results Advanced age of the patient, recipient cytomegalovirus seropositivity, unrelated donor status, human leukocyte antigen mismatch and lower doses of transplanted CD34(+) cells (<= 6.4x10(6)/kg) significantly increased the risk of cytopenias after day 28. Non-myeloablative hematopoietic cell transplantation had protective effects on anemia and thrombocytopenia after day 28 (adjusted odds ratio 0.76, probability value of 0.05 and adjusted odds ratio 0.31, probability value of <0.0001, respectively) but not on overall or ganciclovir-related neutropenia. This lack of protection appeared to be due to the use of mycophenolate mofetil in the majority of recipients of non-myeloablative hematopoietic cell transplants. Peripheral blood stem cells did not confer protection from cytopenias when compared to bone marrow. Conclusions Elderly patients appear to be more prone to cumulative toxicities of post-transplant drug regimens, but non-myeloablative conditioning, optimized human leukocyte antigen matching, and higher doses of CD34(+) cell infusions may reduce the risk of cytopenia after day 28.