Background: The management of rectal cancer has evolved toward response-adapted strategies, including organ preservation in selected patients achieving a clinical complete response (cCR) after neoadjuvant treatment. However, most available evidence derives from clinical trials, and data from real-world clinical practice remain limited. Methods: We conducted a retrospective observational cohort study including consecutive patients with rectal adenocarcinoma treated at a tertiary referral center between January 2021 and December 2025. Baseline clinical, tumor-related, and treatment characteristics were collected. Tumor response was assessed using clinical, endoscopic, and radiological criteria. The primary endpoint was the rate of clinical complete response and the implementation of watch-and-wait strategies. Secondary endpoints included recurrence patterns and exploratory oncologic outcomes according to baseline tumor characteristics. Results: A total of 229 patients were identified, of whom 148 were evaluable for treatment response. Clinical complete response was documented in 56 patients (37.8%), and a watch-and-wait strategy was implemented in 42 patients (28.4%). Higher cCR rates were observed in patients with stage I–II disease and in tumors measuring < 4 cm on baseline magnetic resonance imaging, with cCR rates exceeding 55% in this subgroup. Tumors ≥ 4 cm showed substantially lower response rates. Clinical complete responses were observed across both short-course radiotherapy plus chemotherapy and long-course chemoradiotherapy regimens in patients with small tumors and early-stage disease. Tumor distance from the anal verge was not consistently associated with response. With a median follow-up of 26 months in the watch-and-wait group, five recurrences were observed, including three local recurrences. Conclusions: In this real-world cohort, baseline tumor size and clinical stage were the main determinants of clinical complete response and eligibility for organ-preservation strategies in rectal cancer. Small tumors (<4 cm) showed high response rates regardless of neoadjuvant regimen. These findings support response-adapted, individualized treatment strategies and highlight the importance of tumor burden in selecting candidates for non-operative management in routine clinical practice.