Primary mediastinal B-cell lymphoma (PMBCL) is an uncommon disease, consisting of 2–4% of non-Hodgkin lymphomas. Radiotherapy-free DA-EPOCH-R and R-CHOP plus radiotherapy (RT) have been the upfront standard regimens worldwide. However, performing DA-EPOCH-R in resource-constrained settings can be burdensome, especially in low/middle-income countries, where data on PMBCL are still largely unknown. We retrospectively analyzed 93 patients with PMBCL diagnosed between 2008 and 2018 with the intention of comparing the characteristics of the patients and the results obtained with each protocol and to verify if the use of less intensive chemotherapy is still possible to be used. The median age was 28 years, 59.1% were female, 42.3% were in advanced stages, and 92.1% were with bulky disease. DA-EPOCH-R (41.9%), R-CHOP (35.5%), and R-CHOEP (22.6%) were the regimens used, and no difference was observed in the characteristics of the patients. After four cycles of chemotherapy, complete response (CR), partial response (PR), and progressive disease (PD) rates were 40%, 55.7%, and 4.5%, respectively. At the end of treatment, metabolic CR and PD rates were 56.8% and 11.1%. RT was performed in 42.1% of DA-EPOCH-R, 75% of R-CHOP, and 83% of R-CHOEP, and switched PR to CR in 73.7%. Estimated 5-year PFS and OS were 77.2% and 77.4%, respectively. Only LDH levels remained independently associated with PFS, and type of treatment was not associated with OS, PFS, or relapse rate. Therefore, we conclude that in a resource-constrained setting, R-CHOP or R-CHOEP could be still safely adopted in upfront treatment for PMBCL.