Background: Treatment effects may differ between trials and community settings, in part due to underrepresentation of certain patient subgroups in trials. We used a hybrid approach combining clinical trial and real-world data to compare the effectiveness of adjuvant FOLFOX vs 5FU for stage II-III colon cancer in community oncology practice. Methods: We used Multicenter International Study of Oxaliplatin/5FU-LV in the Adjuvant Treatment of Colon Cancer (MOSAIC) combined with patients who met trial eligibility criteria within US Oncology from 1/1/2008-5/31/2019. In the combined data, we used logistic regression to estimate the probability of trial enrollment as a function of age, sex, substage, body mass index (BMI), and performance status. We estimated inverse odds of sampling weights and weighted MOSAIC participants to reflect three US Oncology populations: 1) patients meeting trial eligibility, 2) stage III patients, and 3) stage III patients initiating FOLFOX. Within the weighted trial populations, we estimated mortality hazard ratios (HRs) and bootstrapped 95% confidence intervals (CIs) comparing FOLFOX with 5FU. Results: There were 2246 MOSAIC participants and 9335 US Oncology patients. MOSAIC participants were younger, had more stage II cancer, lower BMI, and worse performance status compared with US Oncology patients. After weighting MOSAIC participants to reflect the US Oncology populations, the HRs were attenuated (Table) compared with the original MOSAIC estimate (HR = 0.84; 0.71,1.00). Conclusions: When differences between trial and clinical populations exist and response to therapy varies across subgroups, treatment efficacy can differ from clinical effectiveness. Compared with trial results, we found that effectiveness of FOLFOX versus 5FU was attenuated in community oncology practice.