The purpose of this study is to examine the factorial structure of the Brief Symptom Inventory 18 (BSI-18) and test its measurement invariance among different drug using populations. A total sample of 710 drug users was recruited using respondent-drive sampling (RDS) from three states: Ohio (n = 248), Arkansas (n = 237), and Kentucky (n = 225). The results of confirmatory factor analysis (CFA) show: 1) the BSI-18 has a three-factor structure (somatization, depression, and anxiety) with an underlying second-order factor (global severity index of distress); and 2) its factorial structure and metric (factor loadings) are invariant across populations under study. However, the scalars (intercepts) of the BSI-18 items are not invariant, and the means of the latent factors also varied across populations. Our findings provide evidence of a valid factorial structure of the BSI-18 that can be readily applied to studying drug using populations.