The purpose of this study was to assess the clinicopathologic characteristics and outcomes in patients with diffuse large B-cell lymphoma (DLBCL) of the testis, and to assess the impact of changes in the therapeutic approach that have occurred over the years. We reviewed the medical records of 75 patients between 1964 and 2008. Factors analyzed included: age, clinical stage, B-symptoms, serum levels of lactate dehydrogenase (LDH), beta(2)-microglobulin, treatment received, and outcome. Immunophenotypic data were available for 43 cases, all of which showed B-cell lineage. On univariate analysis, stages III and IV (p = 0.042), elevated serum LDH (p = 0.014), B-symptoms (p = 0.003), and high-intermediate or high International Prognostic Index (IPI) score (p = 0.010) were associated with a significantly decreased overall survival (OS) and progression-free survival (PFS). The 5-year OS and PFS for patients after 2000, treated predominantly with R-CHOP, intrathecal chemotherapy (ITC), and scrotal radiotherapy (RT), were 86.6% and 59.3%, respectively. This is compared to 56.3% and 51.7%, respectively, for patients treated between 1977 and 1999 with doxorubicin based chemotherapy without rituximab, who were not uniformly treated with ITC. Patients treated prior to 1977 had an OS and PFS of 15.4% and 15.4%, respectively, and were not treated with doxorubicin based chemotherapy or ITC (p = 0.019 for OS and p = 0.138 for PFS). Advanced stage, elevated serum LDH, B-symptoms, and high IPI are poor prognostic markers. R-CHOP based chemotherapy with intrathecal chemotherapy and scrotal RT is associated with an improved OS.