Background Systemic inflammation (SI) and insulin resistance (IR) are correlated to the progression of gastrointestinal (GI) cancer. Therefore, this study aimed to analyze the potential clinical value of the C-reactive protein-triglyceride-glucose index (CTI) in relation to SI and IR in patients with GI cancer.Methods This prospective cohort study included patients with GI cancer. Patient data were collected from Fujian Cancer Hospital as an external validation cohort. Prognostic AUC, time-dependent ROC curve, C-index, and calibration curve analyses were used to predict the efficacy and accuracy of CTI survival prediction. Multivariate survival analysis was performed to evaluate the potential prognostic value of the CTI. Multiple logistic regression was performed to evaluate the relationship between the CTI and 90-day and 180-day mortalities.Results We divided 1520 patients with GI cancer (mean age, 60.39 +/- 11.3 years; male sex, 67%) into a training cohort and internal validation cohort; the external validation cohort included 476 patients. Prognostic AUC, time-dependent ROC curve, C-index, and calibration curve analyses of all cohorts indicated that the CTI could reliably and accurately predict the short- and long-term survival outcomes of patients with GI cancer. Multivariate survival analysis showed that for each standard deviation increase in the CTI, the risk of death increased by 32%, 21%, and 40% in the training, internal validation, and external validation cohorts, respectively. A high CTI was correlated to worse survival in patients with GI cancer (training cohort, hazard ratio [HR]=1.67, 95% confidence interval [CI]=1.35-2.08; internal validation cohort, HR=1.51, 95% CI=1.07-2.14, and external validation cohort, HR=1.59, 95% CI=1.18-2.13). In different tumor subgroups, a high CTI predicted worse survival outcomes for upper GI cancer (HR=1.54, 95% CI=1.18-2.01) and lower GI cancer (HR=1.98, 95% CI=1.36-2.86). Multivariate logistic regression analysis showed that a high CTI was positively correlated with 90-day (odds ratio [OR]=3.25, 95% CI=1.75-6.23) and 180-day mortalities (OR=2.66, 95% CI=1.72-4.15).Conclusions The CTI is related to SI and IR and can predict the short- and long-term prognosis of patients with GI cancer. Evaluation of the CTI could provide clinicians with an effective tool for predicting the prognosis of patients with GI cancer.Clinical trial registration https://www.chictr.org.cn/showproj.html?proj=31813, identifier ChiCTR1800020329.