Abstract Background Per CDC, C. difficile is an urgent microbial threat. Despite use of CDC diagnostic criteria, 2-step testing protocol and antimicrobial stewardship interventions limiting broad spectrum antimicrobial use, we witnessed an increase in infections in 2022, therefore, additional interventions were implemented. Methods A multifaceted QI intervention program to improve IPC (infection prevention and control) practices was implemented in July 2022 at a 160-bed tertiary care center serving the tristate area of Iowa, South Dakota and Nebraska. Interventions included: auditing and real time observations for health care personnel (HCP) hand hygiene compliance; monitoring soap/sanitizer usage; educational interventions including posters posted throughout the hospital emphasizing hand hygiene, “A clean in and clean out” approach and contact precautions reminders posted in patient rooms/nursing stations, weekly nursing huddles focused on nursing and ancillary staff education, provider counseling and continued coaching. Pre-intervention period (P1: 1/10/2021- 6/30/2022) was compared with Intervention period (P2: 07/01/2022-3/31/2023) for hand hygiene compliance and C. difficile infection rates. Results Overall adequate hand hygiene compliance rates for all health care personnel (HCP) increased from 71% during P1 to 85% during P2 (P< 0.05). All categories of HCP showed a significant improvement in hand hygiene compliance from P1 to P2, with rates for physicians increasing from 74% to 92% (p< 0.05), nurses from 68% to 94% (p< 0.001); nurse practitioners/physician assistants from 75% to 90% (p< 0.05), ancillary staff (chaplain, medical technicians, social workers) from 60% to 89% (p< 0.01)]. Hand hygiene product use increased significantly and soap usage alone increased from 45% to 75% in P2 (p< 0.05). C. difficile infections declined significantly from a mean of 1.9 infections per 1000 patient days during P1 to 0.5 infections per 1000 patient days during P2 (p< 0.001); SIR (Standardized infection ratio) decreased from 1.14 during P1 to 0.4 during P2 (p< 0.01). No C. difficile related mortality was observed. Conclusion With implementation of multifaceted IPC interventions, significantly improved hand hygiene rates and a significant decline in C. difficile infections were observed. Disclosures All Authors: No reported disclosures