Background: Substance use disorders (SUDs), including substance dependence or abuse, have a tremendous impact on individuals, families, communities, and governments. Objective: The purpose of this study was to investigate the prevalence of SUDs in Yazd Greater Area during 2014-2015.Method: This study uses data from the Yazd Health Study (YaHS) recruitment phase which was conducted from 2014 to 2015, to investigate the epidemiology of SUDs among 20-70 year-old adults. We studied 9965 participants 20-70 years old who lived in Yazd Greater Area. Data were collected using a validated questionnaire. Results: The age-adjusted prevalence of illicit substance use was 6.2% (95% CI: 5%-7.4%). for men and 2.5% (95% CI: 1.7%-3.6%) for women. The substance use was significantly correlated with age (r= -0.29, p=0.006), educational level (r= -0.24, p=0.021), tobacco smoking (r= 0.23, p= 0.001), and sex (r= -0.98, p=0.001), But with hookah smoking had no significant relationship (r= -0.01, p=0.891). 35.6% of those consuming drugs had a previous history of addiction treatment. Also, the prevalence of substance use was greater in elders. Conclusion: This study indicated that the prevalence of substance use in adults of Yazd Greater Area which was correlated to the factors including consumption of cigarettes, age, and sex. The prevalence of various addictions is slightly higher than the rest of Iran.