OBJECTIVES: Therapy-related myelodysplastic syndromes and acute myeloid leukemia (t-MDS/AML) are devastating long-term complications of cancer therapy. Evidence suggests that white blood cell growth factors (CSFs) may increase risk of t-MDS/AML among patients (pts) receiving chemotherapy, possibly because they stimulate the proliferation and differentiation of hematopoietic stem cells and also interfere with apoptosis. The purpose of this retrospective study was to evaluate the association between CSF use and t-MDS/AML among a large population-based cohort of elderly non-Hodgkin’s lymphoma (NHL) pts treated with chemotherapy. METHODS: NHL pts were identified from the Surveillance, Epidemiology, and End Results-Medicare database diagnosed from 1992 to 2002 who received chemotherapy within 12 months of diagnosis. Pts were followed from their initial chemotherapy until t-MDS/AML development, death, or end of study period (December 31, 2006). Kaplan-Meier and Cox proportional hazards analyses were used to evaluate the association between CSF use and t-MDS/AML. RESULTS: A total of 13,203 pts were identified. Overall, 40% (n=5,266) received CSF. 272 (5.2%) pts receiving CSF developed t-MDS/AML vs. 230 (2.9%) who did not receive CSF (log-rank p<0.0001). In a multivariable Cox regression analysis adjusting for gender, histology, stage, comorbidities, chemotherapy dates, and chemotherapy agent, CSF use was independently associated with a 53% increased risk of t-MDS/AML (HR 1.53; 95% CI 1.26 – 1.84). A dose-response relationship was observed, with t-MDS/AML risk increasing by quartile of CSF claims. In an evaluation of plausible biologic interactions, we found that pts receiving CSF and antimetabolite chemotherapy (n=1,567 pts) had a 2.5 fold increased risk of t-MDS/AML (HR 2.49; 95% CI 1.91 – 3.26) vs. pts who received neither agent (p-interaction=0.04). CONCLUSIONS: Our findings suggest that CSF use among elderly NHL chemotherapy pts chemo may increase risk of t-MDS/AML, even though absolute risk is low. Future studies are necessary to verify these results and to determine the clinical implications of the observed interaction between CSF use and antimetabolite chemotherapy.