Background: Methicillin-resistant Staphylococcus aureus (MRSA) is a growing clinical problem in rehabilitation hospitals, where patients stay for extended periods for intensive rehabilitation therapy. In addition to cutaneous sites, the nares could be a source for nosocomial MRSA transmission. Decolonization of nasal and cutaneous reservoirs could reduce MRSA acquisition. We evaluated the effectiveness of topical intranasal octenidine gel, coupled with universal chlorhexidine baths, in reducing MRSA acquisition in an extended-care facility. Methods: We conducted a quasi-experimental before-and-after study from January 2013 to June 2019. All patients admitted to a 100-bed rehabilitation hospital specialized in stroke and trauma care in Singapore were screened for MRSA colonization on admission. Patients screened negative for MRSA were subsequently screened at discharge for MRSA acquisition. Screening swabs were obtained from the nares, axillae, and groin and were cultured on selective chromogenic agar. Patients who tested positive for MRSA from clinical samples collected >3 days after admission were also considered to have hospital-acquired MRSA. Universal chlorhexidine baths were implemented throughout the study period. Intranasal application of octenidine gel for MRSA colonizers for use for 5 days from admission was added to the hospital’s protocol beginning in September 2017. An interrupted time series with segmented regression analysis was performed to evaluate the trends in MRSA acquisition before the intervention (January 2013–July 2017) and after the intervention (September 2017–June 2019) with intranasal octenidine. August 2017 was excluded from the analysis because the intervention commenced midmonth. Results: In total, 77 observational months (55 before the intervention and 22 after the intervention) were included. The mean monthly MRSA acquisition rates were 7.0 per 1,000 patient days before the intervention and 4.4 per 1,000 patient days after the intervention (P < .001), with a mean number of patient days of 2,516.3 per month before the intervention and 2,427.2 per month after the intervention (P = .0172). The mean monthly number of MRSA-colonized patients on admission to the hospital decreased from 24.8 before the intervention to 18.7 after the intervention (P < .001). Mean monthly hand hygiene compliance rate increased significantly from 65.7% before the intervention to 87.4% after the intervention (P < .001). After adjusting for the number of MRSA-colonized patients on admission and hand hygiene compliance rates, a constant trend was observed from January 2013 to July 2017 (adjusted mean coefficient, 0.012; 95% CI, −0.037 to 0.06), with an immediate drop in September 2017 (adjusted mean coefficient, −2.145; 95% CI, −0.248 to −0.002; P = .033), followed by a significant reduction in MRSA acquisition after the intervention from September 2017 through June 2019 (adjusted mean coefficient, −0.125; 95% CI, -4.109 to -0.181; P = .047). Conclusions: Topical intranasal octenidine, coupled with universal chlorhexidine baths, can reduce MRSA acquisition in extended-care facilities. Further studies should be conducted to validate the findings in other healthcare settings.