Background: Providing population-based data on awareness, attitude and practice of drug and stimulant use has policy implications. A national study was conducted among Iranian general population to explore life time prevalence, awareness and attitudes toward opioids and stimulant use. Methods: We recruited subjects from 5 provinces with heterogenic pattern of drug use. Participants were selected using stratified multistage cluster sampling. Data were collected using a validated self-administered questionnaire. Logistic regression model was applied to identify the variables that are associated with drug and stimulant use. Results: In total 2065 respondents including 1155 men (33.96 ± 10.40 years old) and 910 women (35.45 ± 12.21 years old) were recruited. Two-third of respondents had good awareness about adverse effects of opioid use. Corresponding figure in terms of stimulants was 81.4%. Almost 95% of participants reported a negative attitude towards either opioid or stimulant use. The lifetime prevalence of opioid use and stimulant use were 12.9% (men: 21.5%, women: 4.0%) and 7.3% (men: 9.6%, women: 4.9%), respectively. Gender (adjusted odds ratio [AOR]M/W=6.92; 95% CI: 2.92, 16.42), education (AORundergraduate/diploma or less =0.49; 95% CI: 0.26, 0.90), and marital status (AORothers/single=2.13; 95% CI: 1.36, 3.33) were significantly related with opioid use. With respect to stimulant use, age was negatively associated with the outcome (AOR60+/20-29 years = 0.08: 95% CI; 0.01, 0.98) and men were 2 times more likely than women to use stimulants (ORM/W=2.15: 95% CI: 0.83, 5.56). In addition, marital status (AOROthers/singles = 3.45; 95% CI: 1.09, 10.93), and awareness (AORWeak and moderate/good =0.40; 95% CI: 0.25, 0.61) were independently correlated with stimulants use. Conclusion: While the attitude of Iranian adults toward opioid and stimulant use was negative, their awareness was not that adequate to prevent the drug use. Men and those with lower socio-economic status (SES) should be the focus of health promotion programs regarding opioid use. However, regarding stimulants use, promotion programs should target younger age groups and those with higher SES status.