Background: Healthcare-associated infections (HAIs) remain a persistent threat to patient safety in acute care settings worldwide, and healthcare facilities in Makkah, Saudi Arabia are no exception. The city's unique demographic pressures, including year-round patient influx and seasonal peaks during Hajj and Umrah, place extraordinary demands on hospital infection control systems. Despite global progress in infection prevention and control (IPC), evidence regarding the effectiveness of structured IPC programmes at the departmental level within Saudi tertiary hospitals remains insufficiently characterised.

Objectives: This study sought to evaluate the role of the infection control system in reducing HAI rates across five medical departments of two tertiary-level hospitals in Makkah, to assess healthcare worker compliance with IPC standards, and to identify risk factors that significantly predict HAI occurrence.

Methods: A quantitative cross-sectional observational design was employed. A total of 400 patient records and corresponding staff compliance observations were collected from January to June 2024. Departments included the Surgical ICU, Medical ICU, Orthopedic Ward, Oncology Ward, and General Medicine Ward. Data encompassed HAI occurrence, compliance with hand hygiene, PPE use, sterile technique, environmental disinfection, isolation protocols, and waste management. Binary logistic regression was applied to identify independent predictors of HAI.

Results: The overall HAI rate was 15.0% (n = 60). Catheter-associated urinary tract infections (CAUTI) accounted for the largest proportion (30.0%), followed by ventilator-associated pneumonia (VAP) at 23.3%. Full compliance with hand hygiene stood at 61.5%, and PPE utilisation compliance was 57.2%. Sterile technique showed the highest compliance rate at 72.0%. Logistic regression identified inadequate IPC training (OR = 3.42, p < 0.001), insufficient hand hygiene compliance (OR = 2.87, p < 0.001), and absence of a dedicated IPC committee (OR = 2.15, p = 0.009) as significant independent predictors.

Conclusion: Structured and consistently enforced IPC systems are central to reducing HAI burden in Makkah's healthcare facilities. Strengthening IPC training programmes, formalising compliance monitoring, and establishing dedicated infection control committees are essential policy actions. These findings inform both local healthcare management and broader regional strategies for HAI prevention.