This paper explores how personality factors affect substance use disorders (SUDs) using explanatory item response modeling (EIRM). A total of 606 Chinese illicit drug users participated in our study. After removing the cases with missing values on the covariate measures, a final sample of 573 participants was used for data analysis. The Diagnostic and Statistical Manual of Mental Disorders (DSM-5) was used to measure the illicit drug users' SUD level. Four personality factors-anxiety sensitivity, impulsivity, sensation seeking and hopelessness-along with gender and alcohol use were included in EIRM as person covariates. The results indicated that gender, alcohol use, and their interaction significantly predicted the SUD level. The only personality factor that strongly predicted the SUD level was sensation seeking. In addition, the interaction between gender and hopelessness was also found to be a significant predictor of the SUD level, indicating that the negative effect of hopelessness on SUD is stronger for women than for men. The findings suggest that sensation seeking plays an important role in influencing SUDs, and thus, it should be considered when designing intervention or screening procedures for potential illicit drug users. In addition, several DSM-5 SUD symptoms were found to exhibit differential effects by gender, alcohol use, and personality factors. The possible explanations were discussed.