This study aimed to identify differences in risk factors for infant mortality in five cities, one from each region of Brazil. This was a case-control study with cases defined as deaths in infants less than one year of age in the Mortality Information System (SIM) and Information System on Live Births (SINASC) and controls as live born infants recorded in the SINASC database and who had not died in the first year. Risk factors were estimated by univariate and multivariate analysis, using hierarchical logistic models. The main determinants of infant mortality were biological factors (low Apgar score, low birth weight, prematurity, and congenital malformations) mediated by socioeconomic factors (education, marital status, and race/color) and prenatal care conditions (prenatal visits). Despite agreement on the determinants of infant mortality among the five cities, some regional differences were observed, expressing infant mortality associated with inequalities in socioeconomic conditions and access to health services.