Environmental disinfection with continuously antimicrobial surfaces could offer superior control of surface bioburden. We sought to decide the efficacy of photocatalyst antimicrobial coating in reducing methicillin-resistant Staphylococcus aureus (MRSA) acquisition in high incidence setting. We performed prospective cohort study involving patients hospitalized in medical intensive care unit. A titanium dioxide-based photocatalyst was coated on high touch surfaces and walls. Five months of pre-intervention data were compared with five months of post-intervention data. The incidence rates of multidrug-resistant organism acquisition and the rates of hospital-acquired blood stream infection, pneumonia, urinary tract infection, and Clostridium difficile-associated diseases were compared using Cox proportional hazards regression analysis. In total, 621 patients were included. There was significant decrease in MRSA acquisition rate after photocatalyst coating (hazard ratio, 0.37; 95% confidence interval, 0.14-0.99; p = 0.04). However, clinical identification of vancomycin-resistant Enterococcus spp. and multidrug-resistant Acinetobacter baumannii did not decrease significantly. The hazard of contracting hospital-acquired pneumonia during the intervention period compared to baseline period was 0.46 (95% confidence interval, 0.23-0.94; p = 0.03). In conclusion, MRSA rate was significantly reduced after photocatalyst coating. We provide evidence that photocatalyst disinfection can be an adjunctive measure to control MRSA acquisition in high-incidence settings. ISRCTN Registry ( ISRCTN31972004 ). Registered retrospectively on November 19, 2018.