Homeless people are usually prone to be infected with multiple infectious diseases such as human immunodeficiency virus, hepatitis B virus, and hepatitis C virus, as well as syphilis. In this cross-sectional study, using a questionnaire and enzyme-linked immunosorbant assay, we evaluated the seroprevalance of hepatitis B and C viruses, human immunodeficiency virus, and syphilis, as well as their risk factors in 202 homeless men. A total of 70 (34.7%), 87 (42.8%), and 13 (6.4%) subjects were infected with hepatitis B, hepatitis C and human immunodeficiency viruses, respectively. Ten (0.5%) had a simultaneous infection with hepatitis B and C viruses and human immunodeficiency virus. Only one participant was seropositive for rapid plasma reagin. History of smoking and opium addiction was present in 144 (71.6%) and 109 (54.2%) subjects, respectively. Although all human immunodeficiency virus-positive subjects were hepatitis C virus positive, 10 (76.9%) had a history of intravenous drug abuse. Risk factors including intravenous drug abuse (P<0.005) and imprisonment (P<0.05) were significantly associated with all the three infections. We found no significant association between high-risk sexual behavior and these infections. Although syphilis seems not to be an important risk factor among homeless adults, all hepatitis B, hepatitis C, and human immunodeficiency virus infections have quite noticeable frequencies among Iranian subjects. History of intravenous drug abuse should be taken into account in screening of homeless people.