We performed a retrospective cohort analysis of 701 (533 white and 144 black) patients with diffuse large B-cell lymphoma (DLBCL) treated at two referral centers in southern United States between 1981 and 2010. Median age of diagnosis for blacks was 50 years vs. 57 years for whites (p < 0.001). A greater percentage of blacks presented with elevated lactate dehydrogenase levels, B-symptoms and performance status ≥ 2. More whites (8%) than blacks (3%) had a positive family history of lymphoma (p = 0.048). There were no racial differences in the use of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; 52% black vs. 47% white, p = 0.73). While black race predicted worse survival among patients treated with CHOP (hazard ratio [HR] 1.8, p < 0.001), treatment with R-CHOP was associated with improved survival irrespective of race (HR 0.61, p = 0.01). Future studies should examine biological differences that may underlie the observed racial differences in presentation and outcome.