Background: S0221 investigated weekly vs q 2 week dosing of doxorubicin/cyclophosphamide (AC) and paclitaxel (P) in patients (pts) with high risk early breast cancer as previously reported (JCO 33:58-64, 2015). After enrollment of 2716 pts randomization to the two AC arms was stopped for futility and an additional 578 pts received 4 cycles of q 2 week AC and were randomized to P weekly (Pw) or P q 2 weeks (P2). We report updated results of the original trial design and the first report of the 578 pts treated with AC x 4 and Pw x 12 or P2 x 6. Methods: Between December 2003 and November 2010, 2716 pts were randomized in a 2x2 factorial design to 1) 15 weeks of weekly AC (A 24 mg/m2/week and C 60 mg/m2/day po) vs 6 cycles of q 2 week AC (A 60 mg/m2 and C 600 mg/m2) and 2) Pw (paclitaxel 80 mg/m2/week x 12) vs P2 (paclitaxel 175 mg/m2 q 2 weeks x 6), with growth factor support as previously described. After study amendment 578 patients received 4 cycles of q 2 week AC followed by Pw or P2. Updated survival was assessed using log-rank tests and Cox regression models. Results: At a median follow-up of 8.5 years, among the pts treated in the original protocol, there were no significant differences among the four treatments for DFS (p=0.21) or OS (p=0.08). The triple-negative subset had worse DFS (P<0.001) than the HER2-positive or ER/PR+/HER2- subsets, with 5 year DFS of 75% vs 83% and 84%, respectively. While we previously found in the triple negative subset that the arm using q 2 weeks for both AC and paclitaxel was marginally superior, the differences among the arms are no longer significant for DFS (p=0.12) or OS (p=0.11). Among the 578 pts assigned ACx4 and randomized to Pw v P2 there were no overall differences in DFS (p=0.70) or OS (p=0.63) after 4.4 years median follow-up. Conclusions: There were no significant differences in DFS or OS between any of the schedules with extended follow-up in the original cohort and no difference in outcome by paclitaxel schedule for the 578 additional patients in the revised protocol. Either paclitaxel schedule may be recommended, with selection based on toxicity, cost, or patient preference rather than efficacy. Support: NCI grants CA32102, CA38926, CA21115, CA21076, CA77597, CA25224, CA77202, CCSRI15469, and Amgen, Inc. Clinical trial information: NCT00070564