Background: Prediction of prognosis in sepsis is an essential research area aiming to improve disease outcomes. In this study, we investigated the role of the C-reactive protein (CRP)/procalcitonin (PCT) ratio as a prognostic tool in sepsis patients. Materials and methods: This prospective observational study was conducted at the intensive care unit (ICU) of Alexandria Main University Hospital in the period from January to June 2024. One hundred and seventy patients with a diagnosis of sepsis were enrolled. Sequential organ failure assessment (SOFA) score, acute physiology and chronic health evaluation (APACHEII) score and CRP/PCT ratio were calculated on admission (day 1), and as a follow-up on day 3. Patients were subsequently divided into survivor and non-survivor groups, and the data were compared. Results: The CRP/PCT ratio was significantly lower, on admission and on follow-up, in non-survivor patients than in survivor patients. The ratio median (minimum-maximum) in non-survivors was 4.82 (1.51-23.28) vs 11.23 (1.85-136.7) in survivors on admission, and it was 7.37 (2.27-26.36) in non-survivors vs 11.37 (2.78-110.9) in survivors on day 3. The ratio was significantly lower in patients with septic shock than in non-septic shock patients. The ratio had a significant negative correlation with both SOFA and APACHEII scores. The receiver operating characteristic (ROC) curve showed high accuracy of the day 1 CRP/PCT ratio to predict mortality [area under curve (AUC = 0.835)], which is comparable to the day 1 SOFA score (AUC = 0.878) and higher than the day 1 PCT and day 1 APACHE scores. Conclusion: Our results suggest a potential role for the CRP/PCT ratio, on admission and on follow-up, as a marker for predicting prognosis in sepsis patients, where low ratio values can predict poor disease outcome.