Using data collected through venue-based sampling in South Florida from 2004 to 2005 as part of the Centers for Disease Control and Prevention-funded National HIV Behavioral Surveillance Among Men Who Have Sex with Men, we estimate the prevalence of crystal methamphetamine use and its association with high-risk sexual behaviors among a large and diverse sample of men who have sex with men (MSM) residing in South Florida. We also examine how these associations differ between HIV-positive and HIV-negative men. Bivariate analyses were used to assess the characteristics of study participants and their sexual risk behaviors by drug use and self-reported HIV status group. Of 946 MSM participants in South Florida, 18% reported crystal methamphetamine use in the past 12 months. Regardless of self-reported HIV status, crystal methamphetamine users were more likely to report high-risk sexual behaviors, an increased number of non-main sex partners, and being high on drugs and/or alcohol at last sex act with a non-main partner. Our findings indicate that crystal methamphetamine use is prevalent among the MSM population in South Florida, and this prevalence rate is similar, if not higher, than that found in US cities that have been long recognized for having a high rate of crystal methamphetamine use among their MSM populations. Notably, the use of crystal methamphetamine among both HIV-positive and HIV-negative MSM is associated with increased HIV-related risk behaviors.