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Under-five mortality (U5M) is an important indicator of the overall health and development of society. There is a wide gap in U5M among different countries and also within the countries. This study was carried out to assess the prevalence, as well as the socio-demographic, and health-related causes of U5M in the region of study. A cross-sectional study was conducted among all registered cases of U5M in rural areas of Khuzestan province, Iran, during the years 2011 to 2015. To assess the socio-demographic determinants of U5M, the sample surveyed consists of 320 families with at least one under-five death using a multistage random sampling method. Also, this study evaluated the number of variables, which may increase the chance of families to have more than one U5M. U5M was 26 per 1000 live births in 2011, but decreased to 22 per 1000 live births in 2015. With the highest cumulative incidence of 43 in Masjed Soleyman and the lowest of 15 in Dehdez, infant mortality constitutes 76% of all U5M. Prematurity and congenital anomalies were responsible for 46% of all causes of mortality (that is, U5). Maternal age at delivery 35 years (OR = 3.5; 95% CI, 1.29–6.22), marriage duration >9 years (1.85, 1.06–3.21), spouse age gap >5 years (2.32, 1.20–4.50), cesarean section (3.85, 1.19–5.74), delivery interval