Background <p>The relationship between inflammation and tumorigenesis has been widely investigated, with tumor-promoting inflammation proposed as an “enabling characteristic.” However, little is known about the prognostic value of surgery-related inflammation. This study evaluates whether postoperative inflammation affects prognosis in patients operated for colorectal cancer (CRC).</p> Methods <p>Consecutive patients undergoing elective minimally invasive curative surgery for stage I-III CRC between 2014 and 2022 were included. Patients were divided into two groups based on the highest C-reactive protein (CRP) value measured within 30 days from surgery. Receiver operating characteristics curve analysis identified an optimal cutoff of 151.5 mg/L (area under the curve = 0.599), defining low-CRP (L-CRP) and high-CRP (H-CRP) groups. The primary endpoint was recurrence-free survival; secondary endpoints included overall survival (OS), cancer-specific survival (CSS), and recurrence pattern.</p> Results <p>A total of 436 patients were analysed. Recurrence-free survival (<i>p</i> = 0.005) was significantly worse in the H-CRP group, as were OS (<i>p</i> &lt; 0.001) and CSS (<i>p</i> = 0.001). Subgroup analysis confirmed results only in stage III. Regarding pT, no differences were found in early pT patients, while significance was maintained for pT3 and pT4. The H-CRP group showed a higher proportion of locoregional and peritoneal metastases (<i>p</i> = 0.018). On multivariate analysis, H-CRP was an independent risk factor for recurrence (<i>p</i> = 0.02), alongside rectal location (<i>p</i> = 0.001), lymphovascular invasion (<i>p</i> = 0.014), and stage III (<i>p</i> = 0.001).</p> Conclusions <p>This study highlights the potential role of postoperative CRP as a negative prognostic factor for recurrence-free survival following curative resection for CRC.</p>