BackgroundThe global Mpox (formerly, Monkeypox) outbreak is disproportionately affecting the gay and bisexual men having sex with men community.ObjectiveThe aim of this study is to use social media to study country-level variations in topics and sentiments toward Mpox and Two-Spirit, Lesbian, Gay, Bisexual, Transgender, Queer or Questioning, Intersex, Asexual (2SLGBTQIAP+)–related topics. Previous infectious outbreaks have shown that stigma intensifies an outbreak. This work helps health officials control fear and stop discrimination.MethodsIn total, 125,424 Twitter and Facebook posts related to Mpox and the 2SLGBTQIAP+ community were extracted from May 1 to December 25, 2022, using Twitter application programming interface academic accounts and Facebook-scraper tools. The tweets’ main topics were discovered using Latent Dirichlet Allocation in the sklearn library. Thepysentimientopackage was used to find the sentiments of English and Spanish posts, and theCamemBERTpackage was used to recognize the sentiments of French posts. The tweets’ and Facebook posts’ languages were understood using the Twitter application programming interface platform and pycld3 library, respectively. Using ArcGis Online, the hot spots of the geotagged tweets were identified. Mann-WhitneyU, ANOVA, and Dunn tests were used to compare the sentiment polarity of different topics and countries.ResultsThe number of Mpox posts and the number of posts with Mpox and 2SLGBTQIAP+ keywords were 85% correlated (P<.001). Interestingly, the number of posts with Mpox and 2SLGBTQIAP+ keywords had a higher correlation with the number of Mpox cases (correlation=0.36,P<.001) than the number of posts on Mpox (correlation=0.24,P<.001). Of the 10 topics, 8 were aimed at stigmatizing the 2SLGBTQIAP+ community, 3 of which had a significantly lower sentiment score than other topics (ANOVAP<.001). The Mann-WhitneyUtest shows that negative sentiments have a lower intensity than neutral and positive sentiments (P<.001) and neutral sentiments have a lower intensity than positive sentiments (P<.001). In addition, English sentiments have a higher negative and lower neutral and positive intensities than Spanish and French sentiments (P<.001), and Spanish sentiments have a higher negative and lower positive intensities than French sentiments (P<.001). The hot spots of the tweets with Mpox and 2SLGBTQIAP+ keywords were recognized as the United States, the United Kingdom, Canada, Spain, Portugal, India, Ireland, and Italy. Canada was identified as having more tweets with negative polarity and a lower sentiment score (P<.04).ConclusionsThe 2SLGBTQIAP+ community is being widely stigmatized for spreading the Mpox virus on social media. This turns the community into a highly vulnerable population, widens the disparities, increases discrimination, and accelerates the spread of the virus. By identifying the hot spots and key topics of the related tweets, this work helps decision makers and health officials inform more targeted policies.