Combined modality therapy, consisting of chemotherapy (ChT) followed by radiation therapy (RT), is an established treatment paradigm for diffuse large B-cell lymphoma (DLBCL). A British National Lymphoma Investigation randomized trial demonstrated no difference in clinical outcomes, including local control, between 30 Gy and 40-45 Gy. Few patients in this study received rituximab or had PET-CT imaging to assessment ChT response. The hypothesis of this phase II study was that more effective systemic therapy (incorporation of rituximab) and optimal post-ChT response assessment (PET-CT), will allow the RT dose to be reduced from 30 Gy to 20 Gy while maintaining high rates of local control. Eligibility for this institutional review board-approved, phase II prospective trial required histological documentation of DLBCL, receipt of ≥ 4 cycles of a rituximab/anthracycline-containing combination ChT regimen, and a negative post-chemotherapy PET-CT. Deauville criteria were adopted in 2013 with a negative scan defined as scores 1-3 (prior patients were scored retrospectively). Primary CNS lymphoma was excluded. Patients with stage I/II disease were treated comprehensively to all sites of original involvement; treatment fields for those with stage III/IV disease were individualized. RT field design followed principles of involved-site radiation therapy (ISRT). RT dose was 19.8-20 Gy in 1.8-2 Gy fractions. Primary endpoint: 5-year local recurrence-free survival. Secondary endpoints: 5-year progression-free survival (PFS) and overall survival (OS). PFS defined as time from initiation of RT to progression due to lymphoma or death, whichever occurred first and censored at last follow-up date. Kaplan Meier estimates were used to estimate PFS and OS. From 2010-2015, 62 patients were enrolled (34 women, 28 men; median age: 58 years [range, 24-86 years]). Stage distribution: I (24, 39%), II (25, 40%), III (4, 6%), IV (9, 15%). Median largest tumor mass at diagnosis: 5.7 cm (range, 1-20). Bulky disease (defined as ≥7.5 cm or ≥ 10 cm) present in 23 (40%) and 16 (28%) of patients, respectively. ChT: R-CHOP in 58 (94%) and R-EPOCH in 4 (6%). Number of ChT cycles: 4 (n = 25, 40%); 5 (n = 2, 3%); and 6 (n = 35, 57%). Post-ChT Deauville scores: 1 (23, 37%), 2 (23, 37%), 3 (15, 24%), and 4 (1, 2%). Comprehensive RT administered to 4/4 patients with stage III and 6/9 patients with stage IV disease- 3 patient with stage IV disease received RT to only select sites. With a median follow-up of 34 months (range, 1-73), there were no local failures with LRFS of 100%. Systemic lymphoma progression developed in 4 patients with stage I/II disease and 1 with stage IV disease. There were 3 deaths (DLBCL, glioblastoma, unknown). PFS at 3 and 5 years: 92% (95% CI: 86-100%) and 78% (95% CI: 63-97%). OS at 3 and 5 years: 100% and 91% (95% CI: 79-100%). With more effective systemic therapy (R-CHOP) and more refined ChT response assessment (PET-CT), the dose of RT in combined modality treatment programs may be able to be further reduced to 20 Gy.