AIM: This study aimed to investigate the relationship between the Cancer Inflammation Prognostic Index (CIPI) and microsatellite instability (MSI), tumor budding, and prognosis in colorectal cancer cases. METHODS: Patients with stage 1–3 colorectal cancer who underwent curative surgical treatment between May 2020 and January 2022 were included. Serum CIPI was calculated, a cut-off point was established using Receiver Operating Characteristic (ROC) analysis and Patients were divided into two groups according to their CIPI scores: Group 1 (low CIPI) consisted of 94 patients, and Group 2 (high CIPI) consisted of 95 patients. RESULTS: A CIPI score >8.54 predicted mortality with 82.2% sensitivity and 59.7% specificity (area under the curve (AUC): 0.712). There were differences in tumor localization (p = 0.01). Group 2 had higher C-reactive protein (CRP) levels (4.2 vs 11.7, p < 0.001), lower albumin levels (4.1 vs 4, p = 0.04), higher neutrophil counts (3.76 vs 4.83, p = 0.002), and higher levels of carcinoembryonic antigen (CEA) and carbohydrate antigen 19.9 (Ca 19.9) (2.08 vs 8.27, p < 0.001 and 8.85 vs 13.9, p = 0.014, respectively). Tumor diameter was larger in high CIPI group (3 vs 3.8 cm, p = 0.001) , disease-free survival (37.7 vs 27.6 months, p < 0.001) and overall survival (39.6 vs 30.6 months, p < 0.001) were lower in high CIPI group 2. In the multivariate Cox regression analysis, a high CIPI score remained a strong independent predictor of poor overall survival (hazard ratio (HR) = 3.383, 95% confidence interval (CI): 1.445–7.921, p = 0.005) disease-free survival, a high CIPI score again stood out as a critical prognostic factor (HR = 3.280, 95% CI: 1.695–6.347, p < 0.001). CONCLUSIONS: A high CIPI score is associated with poor histopathological features and decreased survival. Closer monitoring or more aggressive treatment might improve prognosis for patients with high CIPI values.