Abstract Background The 2021 update to the IDSA Clostridioides difficile Infection (CDI) guidelines recommended fidaxomicin as the preferred treatment over vancomycin for patients with initial and recurrent CDI. Few studies have examined how treatment patterns and clinical outcomes of hospitalized CDI patients changed after the post-guideline update, or contemporary real-world outcomes of fidaxomicin versus vancomycin. Methods This retrospective, observational study used the PINC AI Healthcare Database on adult patients who received CDI treatment between 1/2020 to 6/2021 (pre-period) and between 10/2021 to 9/2022 (post-period). We examined treatment patterns of fidaxomicin, vancomycin, and metronidazole, and also clinical and healthcare-resource use outcomes of patients treated exclusively with fidaxomicin versus vancomycin using nearest-neighbor propensity matching and hierarchical regression methods. As a sensitivity analysis, we repeated the fidaxomicin versus vancomycin comparisons among patients with recurrent or non-recurrent index infections. Results 45,049 patients with CDI from 779 US hospitals met initial inclusion criteria. Comparing pre-versus post-periods, the proportion of patients treated with fidaxomicin increased from 5.9% to 13.7%, p<0.001, vancomycin use decreased from 87.9% to 82.9%, p<0.001, and metronidazole use decreased from 21.6% to 17.2%, p<0.001. When comparing fidaxomicin versus vancomycin post-period, fidaxomicin was associated with lower CDI recurrence: 6.1% vs 10.2%, p<0.001 and higher sustained clinical response: 91.7% vs 87.8%, p<0.001. 90-day post-discharge costs were not significantly different between groups. Sensitivity analyses showed similar findings. Conclusion Since the 2021 guideline update, fidaxomicin use has increased significantly but could be further utilized given its association with better clinical outcomes and no increase in post-discharge costs.