Background: Advanced source control (once-daily bathing and 4-times daily oral care with chlorhexidine aqueous solution) and thorough environmental cleaning were implemented in response to an increased incidence of colonization and infection with extremely drug-resistant (XDR) Acinetobacter baumannii in a Thai medical intensive care unit (MICU). Methods: During the 12-month baseline period (P1), contact isolation, active surveillance for XDR A baumannii, cohorting of XDR A baumannii patients, twice-daily environmental cleaning with detergent-disinfectant, and antibiotic stewardship were implemented. In the 5.5-month intervention period (P2), additional measures were introduced. Sodium hypochlorite was substituted for detergent-disinfectant, and advanced source control was implemented. All interventions except cleaning with sodium hypochlorite were continued during the 12.5-month follow-up period (P3). Extensive flooding necessitating closure of the hospital for 2 months occurred between P2 and P3. Results: A total of 1,365 patients were studied. Compared with P1 (11.1 cases/1,000 patient-days), the rate of XDR A baumannii clinical isolates declined in P2 (1.74 cases/1,000 patient-days; P < .001) and further in P3 (0.69 cases/1,000 patient-days; P < .001). Compared with P1 (12.15 cases/1,000 patient-days), the rate of XDR A baumannii surveillance isolates also declined in P2 (2.11 cases/1,000 patient-days; P < .001) and P3 (0.98 cases/1,000 patient-days; P < .001). Incidence of nosocomial infections remained stable. Six patients developed chlorhexidine-induced rash (1.4/1,000 patient-days); 31 patients developed mucositis (17.1/1,000 patient-days). Conclusions: These results support advanced source control and thorough environmental cleaning to limit colonization and infection with XDR A baumannii in MICUs in resource-limited settings.