Self-efficacy in mpox (formerly known as monkeypox) prevention plays a pivotal role in promoting preventive behaviors by fostering a sense of control and motivation, especially among men who have sex with men (MSM), the population most affected by mpox in many countries.This study aims to assess the mpox prevention self-efficacy among MSM in China and identify factors influencing it, using a validated mpox prevention self-efficacy scale.From October 2023 to March 2024, a nationwide cross-sectional study was conducted among MSM (aged ≥18 years) across 6 geographic regions in China using a snowball sampling method. The recruited participants (effective response rate=2403/2481, 96.9%) were asked to complete an anonymous questionnaire designed based on prior knowledge of mpox and social cognitive theory. The mpox prevention self-efficacy scale was evaluated for construct validity using exploratory factor analysis and confirmatory factor analysis, and its reliability was assessed using the Cronbach α coefficient. Univariate and multivariable logistic regression analyses were used to examine the factors associated with mpox prevention self-efficacy among MSM.A total of 2403 MSM participants were included, with a mean age of 29 (IQR 19-39) years. Of these, 1228 (51.1%) were aged 25-34 years, 1888 (78.6%) held a college degree or higher, and 2035 (84.7%) were unmarried. The median mpox prevention self-efficacy score was 23 (IQR 18-28). Exploratory factor analysis retained 6 items of the mpox prevention self-efficacy scale. Confirmatory factor analysis confirmed a strong model fit (χ²₅=32.1, n=1225; P<.001; comparative fit index=0.991; root mean square error of approximation=0.067; standardized root mean square residual=0.02; goodness-of-fit index=0.992; normed fit index=0.990; incremental fit index=0.991; Tucker-Lewis index=0.974), with all indices within acceptable ranges. The scale demonstrated good internal consistency, with a Cronbach α of 0.859. The positive factors associated with mpox prevention self-efficacy were mpox-related knowledge (OR 1.107, 95% CI 1.070-1.146), perceived risk awareness (OR 1.338, 95% CI 1.132-1.583), and mpox risk perception (OR 1.154, 95% CI 1.066-1.250), while the negative factor was age, with individuals aged 25 years and older exhibiting lower self-efficacy in mpox prevention (25-34 years: OR 0.789, 95% CI 0.642-0.970; 35-44 years: OR 0.572, 95% CI 0.444-0.736; 45 years and older: OR 0.569, 95% CI 0.394-0.823).These findings highlight the critical role of targeted interventions to enhance mpox prevention self-efficacy, particularly through increasing knowledge, perceived risk awareness, and risk perception. Such interventions are especially important for middle-aged and older MSM, who may experience a decline in self-efficacy. Strengthening self-efficacy in these areas is essential for promoting sustained preventive behaviors, improving mental well-being, and contributing to more effective mpox prevention and control within the MSM community.© Quyige Gao, Shangbin Liu, Muzaibaier Tuerxunjiang, Huifang Xu, Jiechen Zhang, Gang Xu, Jianyu Chen, Yong Cai, Fan Hu, Ying Wang. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org).