Background: Preliminary results of NSABP R-04 indicated that 5-FU and cape have similar pathologic complete response (pCR) outcomes and that the addition of oxaliplatin did not improve pCR. We present PROs comparing 5-FU and cape treatments on quality of life (QoL), convenience of care (CoC), and symptoms. Methods: Clinical stage II or III rectal cancer patients were randomized to receive 5-FU (225mg/m² 5 days/wk) or cape (825 mg/m² 5 days/wk) along with RT (4,500cGy in 25 fractions over 5 wk + boost of 540-1080cGy in 3-6 daily fractions). About half of these patients were also randomized to receive oxaliplatin (50 mg/m² /wk). QoL was assessed by the functional assessment of cancer therapy–colorectal (FACT-C) trial outcome index (TOI) and symptoms were assessed by the fluoropyrimidine specific symptom checklist (SCL) collected at baseline, after chemoradiation before surgery (post therapy), and at 1 year. CoC was assessed by the modified ECOG CoC scale post therapy. Primary hypotheses were to compare 5-FU and cape on the endpoints of change in TOI and SCL baseline to post therapy and CoC at post therapy. P-values, means, and confidence intervals (CI) are adjusted for clinical stage, sex, and intent for sphincter-saving surgery. Results: 625 5-FU and 650 cape patients completed baseline and post therapy data forms. Patient characteristics were similar by treatment. Change in TOI was similar by treatment post therapy (p = .21). Change in SCL post therapy was greater for cape patients than for 5-FU patients (mean difference 1.02, 95% CI 0-2.04, p = .05). CoC was superior with cape compared to 5-FU post therapy (mean difference 3.07, 95% CI 1.31-6.01, p = .002). The change from baseline to post therapy for all FACT-C subscales was similar by treatment. Change in TOI, SCL, and all FACT-C subscales were similar by treatment at the 1-year assessment. Conclusions: PROs indicate that patients treated with 5-FU and cape have similar QoL. Cape provides significantly greater convenience of care but slightly increased symptoms compared to 5-FU. NCI PHS grants U10CA37377, U10CA69974, U10CA12027, and U10CA69651, support from sanofi-aventis and Hoffmann La-Roche.