Abstract Background Guidelines support the use of toxin tests after C. difficile antigen detection or nucleic acid amplification tests (e.g., PCR) to help clinicians distinguish colonization from infection and reduce overdiagnosis but the safety of toxin-based diagnostic approaches remains controversial. Methods Five California hospitals monitored hospitalized adults with C. difficile testing before and after operational changes to reduce test-related overdiagnosis (2016–2018). Four added a toxin test to an existing GDH antigen/PCR-based approach and/or changed reporting to encourage the use of toxin results for clinical decision-making (i.e.,“toxin-dominant reporting”). One used the same test (toxin only) and reporting strategy throughout. All used a standardized tool to document clinical outcomes and treatment four days after testing (i.e., Day 5). Results In total, 1,034 patients had a Day 5 assessment with PCR-dominant reporting (pre-operational changes); 2,511 patients had a Day 5 assessment with toxin-dominant reporting (post-operational changes and single facility with no test change). Fewer Toxin-negative/PCR-positive (Toxin−/PCR+) patients received treatment with toxin-dominant reporting (median change: −52.1% [interquartile range (IQR): −35.1%, −69.1%]; aggregate P < 0.001). Day 5 outcomes were similar or better with toxin-dominant reporting despite less treatment. Patient discharge rates and in hospital diarrheal recovery was greater in the subset of Toxin−/PCR+ patients during the toxin-dominant reporting period: median discharge rate change = 8.8% [IQR: 1.5%, 11.9%] (aggregate P = 0.04); median diarrheal recovery rate change = 11.8% [IQR: 8.8%, 18.2%] (aggregate P = 0.018). Conclusion In a 5-center study, toxin-dominant test result reporting decreased anti-C. difficile treatment and improved discharge rates and diarrheal recovery in Toxin−/PCR+ patients. More work is needed to determine the rate of C. difficile-related adverse events in Toxin−/PCR+ patients. Disclosures All Authors: No reported Disclosures.