Purpose: Drug use is quite common in transgender women, but the mechanisms of the drug use remain unclear. The purpose of this study was to investigate the mediating role of loneliness in perceived stress and the drug use among transgender women.Methods: A cross-sectional survey was conducted from April to September 2018 in Shenyang and Kunming, China, among 247 transgender women. Chinese Perceived Stress Scale, the Chinese version of 8-item UCLA Loneliness Scale, a drug use questionnaire, and a demographic characteristic questionnaire were included in the survey. Descriptive analysis, logistic regression, and mediation analysis were done using SPSS Statistics version 26.0 and Mplus version 8.3.Results: The mean age of transgender women in the study was 33.04 years (standard deviation=8.14). Around 33.20% (n=82) of transgender women reported ever using one kind of drugs, the most commonly used drugs were rush (79.20%), ice (8.50%), and 5-MeO-DIPT (8.50%). Univariate logistic regression showed that perceived stress (odds ratio [OR]=1.73, 95% bootstrap confidence intervals [CI]=1.27-2.36) and loneliness (OR=1.62, 95% CI=1.23-2.13) had a significant association with drug use, all p [ps] <0.01. The effect of perceived stress on drug use was partially mediated by feeling of loneliness (estimate=0.09, standard error=0.04, p<0.05), the mediating effect (0.09) accounted for 27.27% of the total effect (0.33).Conclusion: Perceived stress can positively predict drug use. Loneliness plays an important role in drug use among transgender women.