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Background As the current global resurgence of monkeypox virus infection (MPXVi) continues, the immediate supply of vaccines is lower than the demand. Therefore, prioritization of vaccinations for the highest risk subjects using routine medical records is warranted. Methods This population-based cohort study included all Clalit Health Services (CHS) subjects deemed at moderate-to-high risk for MPXVi: males who purchased HIV-PrEP or tested for sexually transmitted infections since January 2021, aged 25–46 who received Human Papilloma Virus vaccine, or HIV-positive. We defined a high-risk group within the cohort and compared the risk for MPXVi to the moderate-risk group from June 6 (the first known CHS case) until Jul 25, 2022. Results Out of 4.8 million CHS members, 8,089 met the study eligibility criteria (0.18%). During the study period, 54 CHS members tested positive for MPXVi, 51 (94%) of whom were included in the study cohort. The highest risk group included 2,274 (28%) subjects who met the following criteria in 2022: Used HIV-PrEP or erectile dysfunction therapy or were diagnosed with STIs by rectal PCR. The hazard ratio for MPXV infection in the high-risk group compared to the moderate-risk group is 19.35 (95% CI: 8.26–45.36). The sensitivity, specificity, NPV, and PPV for MPXV infection are 88.2%, 72.3%, 99.9%, and 2.0%, respectively. Conclusions Subjects in the highest risk group have a nearly 20-fold risk for MPXV infection compared to the moderate risk group. Our findings may assist in prioritizing new vaccines by promptly identifying high-risk populations without the need for intrusive sexual behavior questioning.

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