Purpose To compare diffusion-weighted magnetic resonance imaging (DW-MRI) with positron emission tomography/computed tomography (PET/CT) for staging and evaluating treatment response in patients with diffuse large B-cell lymphoma (DLBCL). Materials and Methods Institutional review board approval was obtained for this study; all subjects gave informed consent. Twelve patients were imaged before treatment and 8 of these also were imaged after two cycles of chemotherapy using both DW-MRI and PET/CT. Up to six target lesions were selected at baseline for response assessment based on International Working Group criteria (nodes >1.5 cm long diameter and extranodal lesions >1cm long diameter). For pretreatment staging, visual analysis of the numbers of nodal and extranodal lesions based on PET/CT was performed. For interim response assessment after cycle 2 of chemotherapy, residual tumor sites were assessed visually and percentage changes in target lesion size, maximum standardized uptake value (SUVmax) and apparent diffusion coefficient (ADC) from pretreatment values were calculated. Results In 12 patients studied pretreatment, there were 46 nodal and 16 extranodal sites of lymphomatous involvement. Agreement between DW-MRI and PET/CT for overall lesion detection was 97% (60/62 tumor sites; 44/46 nodal and 16/16 extranodal lesions) and for Ann Arbor stage it was 100%. In the 8 patients who had interim assessment, 5 of their 49 tumor sites remained abnormal on visual analysis of both DW-MRI and PET/CT and there was one false-positive on DW-MRI. Of their 24 target lesions, mean pretreatment ADC value, tumor size and SUVmax were 772 μm2/s, 21.3 cm2 and 16.9 g/mL, respectively. At interim assessment of the same 24 target lesions, ADC values increased by 85% tumor size decreased by 74%, and SUVmax decreased by 83% (all p<0.01 versus baseline). Conclusion DW-MRI provides results comparable to those of PET/CT for staging and early response assessment in patients with DLBCL.