Background: The misuse of benzodiazepine tranquilizers is prevalent and is associated with increased risk of overdose when combined with other substances. Yet, little is known about other substance use among those who misuse tranquilizers. Objectives: This study characterized subgroups of individuals with tranquilizer misuse, based on patterns of polysubstance use. Methods: Data were extracted from the 2015-2017 National Survey on Drug Use and Health; adults with past-month tranquilizer misuse were included (N = 1253). We utilized latent class analysis to identify patterns of polysubstance use in the previous month. Results: We identified three distinct latent classes, including the: (1) limited polysubstance use class (approximately 54.6% of the sample), (2) binge alcohol and cannabis use class (28.5% of the sample), and (3) opioid use class (16.9% of the sample). The binge alcohol and cannabis use class and the opioid use class were characterized by high probabilities of other substance misuse, including cocaine and prescription stimulants. Those in the binge alcohol and cannabis use class and the opioid use class reported more motives for tranquilizer misuse and higher rates of sexually transmitted infection, criminal involvement, and suicidal ideation. Those in the opioid use class also had greater psychological distress and higher rates of injection drug use. Conclusions: Nearly half of those with tranquilizer misuse in a general population sample were categorized into one of two high polysubstance use classes, and these two classes were associated with poorer functioning. Findings from these analyses underscore the need to reduce polysubstance use among those who misuse tranquilizers.