BACKGROUND: This is an out-of-pocket costs analysis of ifosfamide, epirubicin, and etoposide (IEV) and etoposide, solu-medrol-methylprednisolone, high-dose ara-C-cytarabine, and platinol-cisplatin (ESHAP) drug regimens in treatment of lymphoma in Iran. METHODS: This cross-sectional study was conducted in Shiraz City. Data were collected using a data-collection form. The social perspective was used to collect cost data. Three types of costs were measured, medical direct costs, non-medical direct costs, and indirect costs. RESULTS: 65 patients were treated with these two methods; 27 patients were treated with IEV and 38 with ESHAP. Moreover, the mean direct cost in IEV and ESHAP regimens in 2014 were 1191.10 ± 610.74 and 1819.57 ± 789.73 United States dollars (USD), respectively. The difference was statistically significant (P < 0.001). CONCLUSION: In this study, costs in the IEV regimen were significantly lower than the ESHAP regimen. This was particularly caused by an earlier discharge of patients under IEV regimen; since these patients experienced a trend toward less neutropenia and, hence, had a trend toward fewer hospitalization days, the related cost was 3451.76 USD with savings of 6479.61 USD compared with the ESHAP regimen. Overall, most of patient’s income was spent on out-of-pocket costs for all expenditures incurred because of lymphoma.