South Africa accounts for more than a sixth of the global population of people infected with HIV and TB, ranking her highest in HIV/TB co-infection worldwide. Remote areas often bear the greatest burden of morbidity and mortality, yet there are spatial differences within rural settings. The primary aim was to investigate HIV/TB mortality determinants and their spatial distribution in the rural Agincourt sub-district for children aged 1-5 years in 2004. Our secondary aim was to model how the associated factors were interrelated as either underlying or proximate factors of child mortality using pathway analysis based on a Mosley-Chen conceptual framework. We conducted a secondary data analysis based on cross-sectional data collected in 2004 from the Agincourt sub-district in rural northeast South Africa. Child HIV/TB death was the outcome measure derived from physician assessed verbal autopsy. Modelling used multiple logit regression models with and without spatial household random effects. Structural equation models were used in modelling the complex relationships between multiple exposures and the outcome (child HIV/TB mortality) as relayed on a conceptual framework. Fifty-four of 6,692 children aged 1-5 years died of HIV/TB, from a total of 5,084 households. Maternal death had the greatest effect on child HIV/TB mortality (adjusted odds ratio=4.00; 95% confidence interval=1.01-15.80). A protective effect was found in households with better socio-economic status and when the child was older. Spatial models disclosed that the areas which experienced the greatest child HIV/TB mortality were those without any health facility. Low socio-economic status and maternal deaths impacted indirectly and directly on child mortality, respectively. These factors are major concerns locally and should be used in formulating interventions to reduce child mortality. Spatial prediction maps can guide policy makers to target interventions where they are most needed.