BACKGROUND: Antimicrobial resistance in Mycoplasma genitalium (MG), a cause of urethritis, is a growing concern. Yet little is known about the geographic distribution of MG resistance in the U.S. or associated clinical outcomes. We evaluated the frequency of MG among men with urethritis, resistance mutations, and post-treatment symptom persistence. METHODS: We enrolled men presenting with urethritis symptoms to 6 U.S. sexually transmitted disease (STD) clinics during June 2017-July 2018; men with urethritis were eligible for follow-up contact and (if persistent symptoms or MG) chart review. Urethral specimens were tested for MG and other bacterial STDs. Mutations in 23S rRNA loci (macrolide-associated mutations [MRMs]) and parC and gyrA (quinolone-associated mutations [QRMs]) were detected by targeted amplification/Sanger sequencing. RESULTS: Among 914 evaluable participants, 28.7% (95% CI 23.8-33.6) had MG. Men with MG were more often black (79.8% vs 66%), <30 years (72.9% vs 56.1%), and reported only female partners (83.7% vs 74.2%) than men without MG. Among MG-positive participants, 64.4% (95% CI 58.2%-70.3%) had MRM, 11.5% (95% CI 7.9-16.0%) had parC mutations, and 0% had gyrA mutations. Among participants treated with azithromycin-based therapy at enrollment and who completed the follow-up survey, persistent symptoms were reported by 25.8% of MG-positive/MRM-positive men, 13% of MG-positive/MRM-negative men, and 17.2% of MG-negative men. CONCLUSIONS: MG infection was common among men with urethritis; MRM prevalence was high among men with MG. Persistent symptoms following treatment were frequent among men with and without MG.