Background: The nature of continuous exposure to the street and its associated lifeâ€‘styles make street children vulnerable to the use of psychoactive substances. Aims: The aim of the present study is to study some social factors of street children in Guwahati city and to ascertain the substance use behavior of the street children. Subjects and Methods: A population based crossâ€‘sectional study conducted during September 2008 to August 2009 among 215 street children between the ages of 5 and 18 years of Guwahati City Assam. The main outcome measures were substance use and its related risk factors prevalent among street children. The data collected were analyzed in Microsoft Office and percentages and Chiâ€‘square tests were used to analyze the variables. Results: Around 174/215 (80.9%) of study participants were substance abusers. It is noteworthy that as the age increases substance use was more common when compared to younger age group. The risk of substance abuse was 1.26 times relatively higher among those who had never been to school and 1.12 times more common in those from a joint family when compared to others. However the correlations were not found to be statistically significant. Substance abuse was 1.19 times more common in case of deaths of both parents and the association was found to be statistically significant (P = 0.02). Presence of step parents and substance use in the family was seen to be a risk factor for substance abuse and the association was highly significant (P < 0.001). The association of substance abuse with duration of street life was found to be highly significant. Majority of the substance users 152/174 (87.4%) were in the habit of sniffing glue and this was followed by smoking 147/174 (84.5%). Conclusion: Substance abuse is an important concern affecting street children. Street and its associated lifeâ€‘styles make street children vulnerable to the use of psychoactive substances. Nonâ€‘ government organizations and Government should come forward to curb this problem and save millions of vulnerable lives.