STUDY OBJECTIVE: The primary objective of our study was to compare the effectiveness of oral cephalosporins versus fluroquinolones and trimethoprim/sulfamethoxazole (TMP-SMX) for the treatment of pyelonephritis in patients discharged home from the emergency department (ED). METHODS: This was a multicenter, retrospective, observational cohort study of 11 geographically diverse US EDs. Patients aged ≥18 years diagnosed with pyelonephritis and discharged home from the ED between January 1, 2021 and October 31, 2023 were included. The primary outcome was treatment failure at 14 days defined as a composite outcome of the following: (1) recurrence of urinary symptoms, (2) repeat ED visit or hospitalization for a urinary tract infection, (3) receipt of a new antibiotic prescription for urinary tract infection. Secondary outcome was appropriateness of empiric treatment based on urine culture susceptibility. RESULTS: Among the 851 patients who met inclusion criteria, 647 patients received a cephalosporin, and 204 patients received an Infectious Diseases Society of America guideline-endorsed first-line treatment (fluroquinolones, TMP-SMX). Overall, baseline characteristics were similar between the 2 cohorts. Rates of treatment failure were not significantly different in the cephalosporin group compared with the fluroquinolone/TMP-SMX groups (17.2% of cephalosporin vs 22.5% of fluroquinolone/TMP-SMX group, difference=5.3%, 95% confidence interval -0.118 to 0.01). After adjusting for potential confounders, cephalosporin use was not associated with treatment failure (odds ratio=0.22, 95% confidence interval 0.03 to 1.95). There was no difference in rates of appropriate empiric treatment based on urine culture susceptibility. CONCLUSION: Oral cephalosporins were associated with similar treatment failure rates compared with Infectious Diseases Society of America guideline-endorsed treatments for the treatment of pyelonephritis in ED patients discharged home.