Background: Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) represents the historical 1^st line treatment standard for DLBCL but fails to cure about 1/3 of patients. While generally ineffective in relapsed DLBCL-NOS, checkpoint inhibitors may have greater promise in untreated, immunocompetent patients. We previously reported safety and early efficacy of pembrolizumab plus RCHOP, noting objective responses in 90% of patients (CR 77%) and a 2-year progression-free survival (PFS) of 83%. We now report 5 year follow up of our study. Methods: Patients age > 18 with untreated DLBCL or grade 3b follicular lymphoma, intended to receive 6 cycles of R-CHOP, were eligible. Pembrolizumab 200 mg IV with R-CHOP was given in 21-day cycles for 6 cycles. For this updated analysis, progression and survival events, and immune-related toxicities, are reported. Additionally, prognostic factors including tumor PD-L1 expression (Qualtek/Merck) were re-analyzed. Results: 30 patients were treated (13/30 with IPI 3-5). Median follow up is now 4.8 years (95% CI, 4.5-5.4). Since our initial report (Smith BJH 2019) we have observed 1 additional relapse (alive after CAR-T therapy) and 2 deaths in remission (1 urothelial carcinoma, 1 respiratory failure in the setting of progressive ILD). 5-year PFS is 71% (CI, 54-94%) and 5-year overall survival 83% (CI, 71-98%). During the study period and at long term follow up, there were 8 total immune-related adverse events (IRAEs) among 7 patients (23%) (Table). Four were treatment-emergent AE (occurred within 90 days of completing treatment): grade 1 hyperthyroidism, grade 2 hyperthyroidism, grade 3 pneumonitis, and grade 3 rash. There were 4 late IRAEs: colitis, paraneoplastic pemphigus, rheumatoid arthritis, and Graves’ disease, occurring at 3, 5, 8, and 46 months after completing treatment, respectively. PD-L1 tumor expression was documented in 19 of 23 (83%) tested patients. At long-term follow up, none of the 19 patients who had any PD-L1 expression have relapsed. Two out of the 4 patients with no PD-L1 expression have relapsed. On univariate analysis, PD-L1 H-score >0 (p<0.0001) was associated with improved PFS. Conclusions: At 5 year follow-up, pembrolizumab plus R-CHOP has led to durable responses in most patients with the best outcomes in PDL1-expressing disease. Furthermore, the safety profile was manageable, with a low rate of grade 3 or higher IRAEs (10%) and no consistent pattern of late events. These data support ongoing strategies incorporating PD-1/PDL-1 inhibitors in 1st line DLBCL therapy and confirmation of predictive biomarkers including tumor PD-L1 expression. Clinical trial information: NCT02541565.