Background Men who have sex with men (MSM) are at high risk for sexually transmitted infections (STI) and often have sex while under the influence of drugs (sexualized drug use). We aimed to identify classes of MSM in Amsterdam and in surrounding urban regions with distinctive patterns of sexualized drug use and their association with STI. Methods In this cross-sectional study, data on MSM were collected at STI clinics in the Netherlands between September-December 2017. Information on drug use, sociodemographics and sexual risk behavior, including lab-confirmed STI (chlamydia, gonorrhea, syphilis and HIV) was collected and compared between Amsterdam and surrounding urban regions. Latent class analysis was used to identify classes with similar drug use patterns, which were then linked to sexual behavior and STI. Results We included 4461 MSM who were a median 35 years old (IQR = 27–47) and mostly Dutch (56.9 %). Use of all drugs was more often reported in Amsterdam compared to surrounding regions (p<0.001). We identified four different classes based on sexualized drug use among Amsterdam participants and three classes in surrounding regions. In both regions, polydrug use classes (compared to classes of no drug use; alcohol use; or few, various drugs) were defined by higher numbers of sexual partners (median range 8–15 vs 4–6, respectively) and higher STI prevalence (range 30.5%–31.8% vs 18.6%–22.8%, respectively). Conclusion Given the high prevalence of risk behavior and STIs, MSM in urban settings partaking in sexualized polydrug use might benefit from tailored outreach, screening, and safe sex and drug use interventions.