Objective: This study aimed to determine the prevalence of epilepsy in prisoners suffering from substance dependence and the relationship between onset of epilepsy and substance dependence in a prison population. Methods: The present cross-sectional study in a prison population was conducted in Central Jail (CJ), New Delhi, India over a period of 3 months. The convenience sample consisted of 900 subjects. The study group consisted of 450 prisoners taken from the deaddiction ward and the rest were placed in the control group. Physical examination and Mini Mental State Examination (MMSE) of subjects were done to make necessary exclusion. Assessment tools were applied in the order starting from MMSE, Basic Socio-demographic Performa, Present State Examination (PSE), and Addiction Severity Index (ASI). Results: The average ages of study and control subjects were 34.5 + 2.3 years (mean + standard deviation) and 35.6 + 3.6 years respectively. Prevalence of epilepsy among substance using prisoners was 1.4 times higher than in non-substance using prisoners. Alcohol, opioid, and cannabis, either alone or in various combinations, were the most commonly used substances. Subjects suffering from epilepsy were likely to have higher chances of consuming three or more substances than those without problem of epilepsy. Study subjects suffering from epilepsy compared with those without epilepsy performed worse in all parameters. This is indicative of higher severity of psychoactive substance dependence. Conclusion: Findings of high prevalence rate of epilepsy and co-morbid substance dependence highlight the need for better screening among epileptic subjects for substance abuse at entry into prison for effective treatment while in custody, and at follow-up on release. Specialist addiction services for prisoners have a considerable impact in a wellplanned intervention programme for prisoners with substance use and comorbid epilepsy. ASEAN Journal of Psychiatry, Vol. 15 (2): July – December 2014: 153-163.