The reasons for differences in outcome between groups of patients with diffuse large cell lymphoma (DLCL) defined by clinical prognostic factors are largely unknown. Measures of cell proliferation may offer a biological explanation for these differences. This study tested the hypothesis that these survival differences between the groups defined by established prognostic factors were due to the proliferative index. The bromodeoxyuridine labeling index (LI), a measure of the S-phase fraction, was prospectively determined on fresh tumor specimens obtained at initial diagnosis in 80 patients with DLCL seen between 1986-1993 at a single institution. Patients were grouped using prognostic factors that were significant in a univariate analysis as well as the International Index (IPI). The LI in each of these groups was compared to determine whether the differences in outcome between the groups could be explained by differences in the LI. The median LI for all patients was 5.1% (range: 0.1-25%). When the predictive effect of the LI on response and survival was analyzed, the LI did not correlate with complete response or disease-free survival (DFS). There was a trend, however, for patients with a lower LI to have a poorer overall survival (p=0.06). When the patients were analyzed using the International Index (IPI), the mean LI for patients in the low-risk, low-intermediate, high-intermediate and high risk groups was 7.1%, 10.0%, 6.4% and 6.6% respectively (p=0.41). When analyzed separately, there was no significant difference in the LI for any of the patient groups defined by significant prognostic factors. The only difference in the LI was that the median LI in patients with T-cell DLCL was significantly lower than the LI in patients with B-cell DLCL (p=0.001) and these patients had an inferior complete response rate (p=0.001), disease-free survival (p=0.003) and overall survival (p=0.015). In this study, the LI, a measure of lymphoma cell proliferation, was not a significant prognostic factor for response, disease-free survival or overall survival. Furthermore, the LI did not explain the differences in outcome between patient groups defined by the IPI. However, a lower LI seen in patients with T-cell DLCL may account for their poorer response to therapy and inferior survival when compared to patients with B-cell DLCL.