We aimed to examine trends and characteristics of substance use (opioid, cocaine, marijuana, and heroin) among hospitalized homeless patients in comparison with other hospitalized patients in 3 states.This was a cross-sectional study, based on the 2007 to 2015 State Inpatient Data of Arizona, Florida, and Washington (n = 32,162,939). Use of opioid, cocaine, marijuana, heroin, respectively, was identified by the International Classification of Diseases, 9th Revision. Multi-level multivariable regressions were performed to estimate relative risk (RR) and 95% confidence intervals (CI). Dependent variables were the use of substances (opioid, cocaine, marijuana, and heroin), respectively. The main independent variable was homeless status. The subgroup analysis by age group was also conducted.Homeless patients were associated with more use of opioid (RR [CI]), 1.23 [1.20-1.26], cocaine 2.55 [2.50-2.60], marijuana 1.43 [1.40-1.46], and heroin 1.57 [1.29-1.91] compared to other hospitalized patients. All hospitalized patients including those who were homeless increased substance use except the use of cocaine (RR [CI]), 0.57 [0.55-0.58] for other patients and 0.60 [0.50-0.74] for homeless patients. In all age subgroups, homeless patients 60 years old or older were more likely to be hospitalized with all 4 types of substance use, especially, cocaine (RR [CI]), 6.33 [5.81-6.90] and heroin 5.86 [2.08-16.52] in comparison with other hospitalized patients.Homeless status is associated with high risks of substance use among hospitalized patients. Homeless elderly are particularly vulnerable to use of hard drugs including cocaine and heroin during the opioid epidemics.