Background: The combination of rituximab plus CHOP chemotherapy (R-CHOP) is widely used as standard of care for DLBCL; however, long-term survival is low in patients (pts) with high (IPI) risk scores. Enzastaurin (ENZ) targets protein kinase C-β (PKCβ), an enzyme correlated with poor pt outcomes in DLBCL. In this trial, we compared the results of first-line treatment with R-CHOP + ENZ to standard R-CHOP. Methods: DLBCL pts were required to have intermediate or high-risk IPI scores (2-5). Pts were randomized (3:2 ratio) to receive six 21-day cycles of either R-CHOP plus ENZ therapy (Arm A) or R-CHOP alone (Arm B). After 6 cycles, responders in Arm A could continue single agent ENZ. An 1125 mg oral loading dose of ENZ was given on Day 2 followed by 500 mg ENZ daily. Response was evaluated (IWG criteria, 1999) q8 weeks. The primary endpoint was progression-free survival (PFS). Randomization of 100 pts allowed detection of an improvement in the PFS at 2 years from 65% (R-CHOP) to 80% with R-CHOP + ENZ (80% power, 1-sided alpha 0.2). This preliminary analysis was performed after all pts had completed R-CHOP chemotherapy, and had been followed for at least one year. Results: Pt characteristics were comparable in Arm A (N=57) and Arm B (N=43). 65 pts (65%) had either high-intermediate (44%) or high (21%) IPI risk scores. The median PFS has not yet been reached; however, the 1-year PFS rate for Arm A was 71% (CI 0.58, 0.84) and Arm B 52% (CI 0.35, 0.69). Overall response rates for Arms A and B were 80.4% and 83.3%, respectively; complete response rates were 35.7% and 26.2%. Most frequent grade 3/4 AEs were neutropenia (56.1% vs 51.1%) and thrombocytopenia (17.5% vs 13.9%) (Arm A vs Arm B). In Arm A 23% and in Arm B 9.3% of pts had grade 3/4 infection-related complications. In Arm A 4 pts died (sepsis 2, pulmonary embolism 1, and ARDS 1) and in Arm B 3 pts (sepsis 2, pneumonia 1). Conclusions: This preliminary analysis suggests an improvement in PFS and complete response rate for pts with intermediate or high risk DLBCL treated with R-CHOP + ENZ when compared to R-CHOP, with comparable toxicity profiles. The final analysis will be conducted after 2-year followup.