Since 1997, rituximab (R) has had a dramatic impact on therapy of NHL. We analyzed R utilization in de novo FL, MCL and DLCL, and the motivation behind this use, using the NCCN NHL outcomes database. This project collects demographic, staging, treatment and outcome information on consecutive pts with NHL seen at 5 geographically diverse NCCN institutions (Dana-Farber, Roswell Park, City of Hope, Fox Chase and MD Anderson). Between 7/2000 and 5/2004, 1028 evaluable pts have been enrolled. R use (+/− chemo) must have occurred within 180 days of presentation, and rates were evaluated in 6-month periods. Pts previously treated or with relapse/transformation within 180 days were excluded. Pts with FL not treated within 180 days (“observation”) were included. Overall, 87% of DLCL pts (N=278) received R, including 116/135 (86%) pts with early stage disease, and 137/162 (85%) pts under age 60. The only significant predictor of R use was year of presentation (P<0.01), (adjusting for IPI, age, 1st line therapy, comorbidity, and center): after 7/01, 93% of pts received R compared with 69% prior to 7/01. Of 167 pts with FL, 52% received R, 11% received chemo only, 10% XRT only, 2% other, and 25% received no therapy. The final FL multivariate logistic regression model included time, stage, chemo, 1st line therapy, B-symptoms, comorbidity, and center. Unlike DLCL, center was a significant predictor of R use (P=0.001); rates of R use in FL varied from 7% to 84% within these 5 centers. Additionally, the overall approach to FL is clearly evolving: as of 7/01, significantly fewer pts were observed (21%) as compared to pre- 7/01 (36%). Of 65 MCL pts, 86% received R within 180 days of presentation. Similar to DLCL, the use of R increased over time: as of 7/01, 92% received R versus prior to 7/01, when only 62% received R. All 5 institutions had active clinical trials for these histologies that incorporated R during this time, however, only 28% of these pts were enrolled on clinical trials. Therefore, despite limited long-term follow-up of confirmatory clinical trials, R was rapidly incorporated into the upfront treatment regimens for the vast majority of pts seen in these NCCN institutions with FL, MCL and DLCL. Despite some variation between centers in FL, adaptation of “standard” R utilization in most institutions predated NCCN guideline inclusion, and occurred while national trials evaluating R benefit were still accruing. Widespread R utilization clearly impacted clinical trial design and accrual. Moreover, if this experience reflects national trends, a potential expenditure of at least $0.5 billion annually is associated with R for de novo NHL. Finally, the impact of widespread R use and changing approaches to FL on developing novel biological agents remains to be defined.