Background: The primary analysis of a phase II randomized trial did not show benefit from IC for overall survival (OS) or pathologic complete response (pathCR). A secondary analysis was done to identify if any subgroups benefited from IC. Methods: 126 patients were randomly assigned to IC plus trimodality or trimodality. Multivariate recursive partitioning analysis (RPA) was applied to identify subgroups with differing OS experience. Additionally, proportional hazards regression with interactions was carried out to identify differential effect of IC. Results: The median follow-up was 6.7 years (range, 3.3 to 9.8 years), and the median OS was 3.8 (95% CI: 2.6, 5.8) years for 126 patients. OS showed univariate association with tumor length (p = 0.03), T stage (p = 0.02), N stage (p = 0.04), clinical stage (p = 0.01), and tumor grade (p < 0.001). IC did not improve OS after additional follow-up (p = 0.13) or the pathCR rate (p = 0.09). However, when tumor grade and IC were modeled together, the effect of IC differed between the two grade groups. Among patients with well/moderate tumor grade (n = 59) IC impressively prolonged OS (74% vs. 50% alive at 5 years, respectively, but not for poor grade (31% vs 28% alive at 5 years, respectively; interaction p = 0.04; IC p = 0.03). RPA confirmed this subgroup; finding 4 EC phenotypes by clinical variables for OS: (1) Very-high risk (poor grade and cN2/N3), (2) High risk (poor grade, cN0/N1, and cIII stage), (3) Moderate risk (poor grade, cN0/N1, and cI/II stage or well/moderate grade without IC), and (4) Low risk (Well/moderate grade and had IC). Patients’ 5-year OS in these subgroups were 11%, 27%, 48%, and 74%, respectively (p < 0.001). Conclusions: The secondary analysis of a randomized trial provides a compelling suggestion that IC may be highly beneficial for low-risk subgroup of EC and a prospective evaluation is warranted.