Introduction: Certain aggressive non-Hodgkin lymphoma (NHL) subtypes are often treated with infusional dose-adjusted rituximab, etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin (DA-R-EPOCH). Unlike other regimens such as rituximab with cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), DA-R-EPOCH requires a central line. In practice, we have observed clinically meaningful line-associated complications (LAC) in patients (pts) treated with DA-R-EPOCH. With the ongoing use of this regimen, we sought to identify the rates and correlates of LAC in this population, and compare them to the rates of LAC in pts with NHL treated with R-CHOP. Methods: We retrospectively identified all pts treated with DA-R-EPOCH at the Wilmot Cancer Institute between 3/2011 and 10/2015. We also identified a concurrent cohort of pts treated with R-CHOP, matching for stage. Our primary endpoint was the rate of LAC, including venous thromboembolism (VTE), chemotherapy extravasation, and line-associated infection (LAI) diagnosed during treatment. Our secondary endpoint was the rate of VTE during therapy. Rates and 95% confidence intervals (95% CI) were calculated for all endpoints, and compared using Fisher's exact test. Univariate logistic regression was used to calculate odds ratios to evaluate potential predictors. Results: A total of 43 pts received DA-R-EPOCH during the study period. A total of 17 pts (39.5%, 95% CI 0.25–0.56) experienced at least 1 LAC: 15 pts (35%, 95% CI 0.21–0.51) had VTE; 3 pts had LAI; and 2 pts with extravasations. A total of 44 pts received R-CHOP during the study period. A total of 8 pts (18.2%, 95% CI 0.08–0.32) experienced at least 1 LAC. Compared to the R-CHOP cohort, pts treated with DA-R-EPOCH experienced a significantly higher rate of LAC (p = 0.03). In the DA-R-EPOCH cohort, grade 3 toxicity was seen in 41% (7/17): 4 pts with VTE, and 3 pts with LAI. Both extravasation events were grade 2, and both occurred with mediports. In univariate analysis, BMI ≥ 35 kg/m2 and using a peripherally inserted central catheter (PICC) line were significantly associated with an increased risk of VTE (p = 0.04 and p = 0.02, respectively). Conclusions: Approximately 40% of pts receiving DA-R-EPOCH therapy for treatment of NHL developed LAC, almost half of whom experienced grade 3 toxicities. The rate of LAC was significantly greater in pts undergoing therapy with DA-R-EPOCH, compared to R-CHOP. Clinicians need to balance these risks when selecting therapy, particularly with the lack of randomized data to support the DA-R-EPOCH approach in many circumstances. Given observed extravasations, when administering DA-R-EPOCH, we avoid mediports in favor of PICC lines; however, this approach carries a significant risk of VTE. Future studies are needed to evaluate the role of prophylactic anticoagulation in this population. Keywords: DA-R-EPOCH; non-Hodgkin lymphoma (NHL); R-CHOP.