BACKGROUND:The incidence of rectal cancer in patients ≤ 50 years of age is increasing. The response to neoadjuvant treatment in patients ≤ 50 years of age is not known. Factors affecting the response to neoadjuvant therapy in this age group have not been evaluated. OBJECTIVE:This study aims to evaluate the rate and identify factors that affect pathologic response to neoadjuvant therapy in patients with early age-of-onset rectal cancer. DESIGN:This study is a retrospective review. SETTING:The investigation was conducted at a tertiary-care cancer referral center. PATIENTS:Included were 193 consecutive patients ≤ 50 years of age with rectal cancer who underwent neoadjuvant therapy followed by surgical resection. INTERVENTIONS:No interventions were performed. MAIN OUTCOME MEASURES:The primary outcome measured was the pathologic response to neoadjuvant treatment. RESULTS:The median age was 44 years, and 34% of the patients were female. The median distance from the anal verge was 7 cm. The median percentage of lumen occupied by tumor was 50%. The median CEA level was 3.5 ng/mL. The median treatment response was 80%. The mean number of lymph nodes examined was 15 per patient. Twenty-two percent of patients had a complete or near-complete (≥ 95%) response to neoadjuvant treatment. Seventy-seven percent of evaluable patients experienced tumor or lymph node downstaging on pathologic examination. The presence of adverse histologic features, percentage of lumen occupied by tumor, and CEA level differed between those with <95% response and those with ≥ 95% response to neoadjuvant therapy, although CEA level was not significant when stage IV patients were excluded. LIMITATIONS:This is a retrospective review with heterogeneity in workup, treatment regimens, and interval to surgery. Long-term oncologic outcomes are not available. CONCLUSIONS:The rate of response to neoadjuvant treatment appears similar in patients with early age-of-onset rectal cancer to non-age-based cohorts in the literature. Adverse histologic features and bulky circumferential tumors may be suggestive of a decreased response to neoadjuvant therapy.