Although childhood mortality rates have been steadily declining in Ghana over the last two decades, the rate of decline has been very slow and uneven. This study compares the determinants of childhood mortality in Ghana for 2003 and 2008. Secondary data from the 2003 and 2008 Ghana Demographic and Health Surveys were used for the study. Bivariate analysis and binary logistic regression were used to examine the relationship between socio-demographic, household/environmental, and biomedical characteristics of mothers and childhood mortality for both survey years. The results show that childhood mortality had a significant relationship with parity, household size, and duration of breastfeeding for both survey years; and that mothers with higher parity; mothers from small size households and mothers who never breast fed were significantly likely to experience childhood mortality compared to their counterparts, for both 2003 and 2008. Furthermore, work status and mosquito bed net use significantly influenced childhood mortality for 2003 while religion and type of birth significantly influenced childhood mortality for 2008. Some socio-demographic, household/environmental as well as biomedical factors actually influenced childhood mortality for both survey periods.