Background <p>Understanding the minimal clinically important difference (MCID) and the factors associated with its deterioration is vital for defining meaningful outcomes and developing shared decision-making approaches. This study examined the temporal evolution of quality of life (QoL), determined the MCID, and identified factors influencing MCID deterioration in patients with colorectal cancer undergoing cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) compared with those undergoing CRS alone.</p> Methods <p>QoL was assessed using EORTC QLQ-C30 and EORTC QLQ-CR29 preoperatively, and at 3, 6, and 12&#xa0;months postoperatively. This prospective cohort study employed the anchor-based method, using the Global Rating of Change Scale to measure MCID for QoL.</p> Results <p>After adjusting for the inverse probability of treatment weighting method, both cohorts exhibited comparable overall covariates. The CRS plus HIPEC group demonstrated a significant net positive effect on QoL measures compared with the CRS-alone group over time (<i>p</i>&#xa0;&lt;&#xa0;0.05). Patients with CRS plus HIPEC had a larger MCID than those with CRS alone for both improvement and deterioration. MCID deterioration was significantly associated with surgical approach, age, sex, body mass index, cancer stage, American Society of Anesthesiologists score, recurrence status, and preoperative QoL (<i>p</i>&#xa0;&lt;&#xa0;0.05).</p> Conclusions <p>CRS plus HIPEC and CRS alone effectively alleviated symptoms and extended survival in our patients with colorectal cancer despite initial deterioration in QoL and morbidities. QoL and symptoms typically improved or returned to baseline within 3&#xa0;months, especially with CRS plus HIPEC. These findings provide crucial evidence for preoperative shared decision making, perioperative care references, and postoperative management strategy planning.</p>