This study, conducted in 12 jurisdictions, evaluated Mpox vaccine effectiveness (VE) among MSM and transgender adults aged 18-49 years.  309 case-patients of confirmed or probable mpox virus or Orthopoxvirus diagnosis were matched to 608 control patients who had visited a sexual health, HIV care, or PrEP clinic.  Participants completed a survey to provide information on demographics, mpox diagnosis and vaccination (history was verified through state registries where available), immunocompromising conditions, and exposures.  Larger proportions of case- than control participants reported recent homelessness (7.9% vs. 2.7%), transactional sex (9.1% vs. 3.3%) and living with HIV (48.1% vs. 24%).  Among participants who did not report living with HIV, a smaller proportion of case participants reported PrEP use (54.4% vs. 66.8%).  Larger proportions of case participants reported an immunocompromising condition or medication (46.6% vs. 26%) and recent close contact with a known mpox case (23% vs. 3.9%).  Larger proportions of case participants had a recent STI (26.2% vs. 13%).  Among 917 participants included in the VE analysis, 22.5% were fully vaccinated, 32.2% were partially vaccinated, and 45.4% were unvaccinated.  After adjustment, VE was 75.2% for partial vs. 85.9% for full vaccination.  Among partially vaccinated participants, VE (by administration route) was 77% for subcutaneous vs. 80.6% for intradermal.  Among fully vaccinated participants, VE was 88.9% for subcutaneous, 80.3% for intradermal, and 86.9% for heterologous administration.  Among participants with an immunocompromising condition, VE was 51% for partial vs. 70.2% for full vaccination (among people without an immunocompromising condition, rates were 72.1% vs. 87.8%).