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In the United States, an estimated 553,000 people are homeless on any given night. Few data provide large-scale, contemporary insight with regard to recent patterns of acute illness in this vulnerable population. We evaluated patterns, causes, and outcomes of acute hospitalization among homeless persons compared with a demographics-standardized and risk-standardized nonhomeless cohort.Retrospective study comparing 185,292 hospitalizations for homeless individuals and 32,322,569 hospitalizations for demographics-standardized nonhomeless individuals between 2007 and 2013 in Massachusetts, Florida, and California. Annual hospitalization rates for homeless persons were calculated and causes of hospitalization were compared with a demographics-standardized nonhomeless cohort. Logistic and linear regression models were used to estimate risk-standardized outcomes.From 2007 to 2013, hospitalizations for the homeless increased in Massachusetts (294 to 420 hospitalizations per 1000 homeless residents), Florida (161 to 240/1000), and California (133 to 164/1000). Homeless patients were on average 46 years of age, often male (76.1%), white (62%), and either uninsured (41.9%) or insured by Medicaid (31.7%). Hospitalizations for homeless persons, compared with demographics-standardized nonhomeless, were more frequently for mental illness and substance use disorder (52% vs. 18%, P<0.001). Homeless compared with risk-standardized nonhomeless individuals had lower in-hospital mortality rates (0.9% vs. 1.2%, P<0.001), longer mean length of stay (6.5 vs. 5.9 d, P<0.001), and lower mean costs per day ($1 535 vs. $1 834, P<0.001).Hospitalizations among homeless persons are rising. Despite greater policy and public health focus over the last few decades, mental illness and substance use remain primary drivers of acute hospitalization among homeless adults. Policy efforts should address barriers to the use of ambulatory care services, and behavioral health services in particular, to help reduce acute care use and improve the long-term health of homeless individuals.