Background: DLBCL is a common lymphoma of older adults, and a potentially curable disorder with the regimen RCHOP (Coiffier, et.al. NEJM,2002). Doxorubicin, a key drug in the regimen, has risk for cardiotoxicity, and thus of concern in older patients (pts) with higher incidence of cardiovascular (CV) disease. In breast cancer pts pegylated liposomal doxorubicin (D) has shown greater cardiac safety and similar efficacy to doxorubicin. We thus replaced doxorubicin with D in RCHOP (DRCOP). Methods: The regimen is: rituximab 375 mg/m2 IV day (d) 1; D 40 mg/m2 IV d 1; cyclophosphamide 750 mg/m2 IV d 1; vincristine 2 mg IV d 1 total dose; prednisone 100 mg/d p.o. d 1-5. Eligibility criteria were: > 60 years of age; untreated confirmed DLBCL (no discordant histology); Ann Arbor stage II-IV; baseline LVEF 50%. CV disease was permitted, if symptoms controlled, but consult at baseline by Cardiologist and at follow-up required. Troponin and brain natriuretic peptide (BNP) levels were monitored. Granulocyte growth factor support recommended (not required). Results: 80 pts total were enrolled on study; 79 were eligible and evaluable for response and toxicity. Characteristics of pts: age 61-94 years (median 71); 41 female. All had at least one cardiac risk factor. Responses were: 55 CR (69%); 14 PR. (17%) At a median follow-up of 2.7 years, 62 are alive (77%), with 78% progression free survival. There were 7 grade 3 adverse cardiac events: 1 drop in LVEF; 4 atrial arrhythmias (reversed); 1 hypotension (reversed); 1 chest pain (reversed). Troponin and BNP changes did not correlate with cardiac events. Other grade 3-4 non-hematologic events: 3 hand-foot syndrome; 4 fatigue; 2 DVT; 2 neuropathy. Only one death occurred on study due to pneumonia, non-neutropenic. The most common grade 3-4 toxicity events were hematologic. Conclusions: DRCOP is an active regimen. In this study of older pts with DLBCL, only one pt had drop in LVEF below normal. Other cardiac events were associated with underlying cardiac conditions, and were reversible. Liposomal doxorubicin should be considered in older patients. Comanagement by a Cardiologist during chemotherapy would be recommended.