Euphorbia ingens is the largest of the succulent tree Euphorbias in Southern Africa. In South Africa, it is most abundant in the northern portion of the country, especially in the Limpopo and North West Provinces. In the mid-nineties, E. ingens were noted to show symptoms of disease, and by 2000 severe mortality had begun to occur in the Limpopo Province. Various factors have been suggested as possible causes of this mortality. We investigated the possible involvement of changes in climate in the sudden die-offs of E. ingens. Four sites within the severely affected Limpopo Province and two sites in the less affected North West Province were included. Nine linear transects were established at each site. Each tree within a transect was scored as alive or dead, and as mature or juvenile. Insect and disease symptoms, and environmental variables were also evaluated. Trees in the Limpopo Province were more severely affected by disease and insects and exhibited higher levels of mortality compared to trees in the North West Province. Analyses of weather data revealed greater upward trends in temperature and downward trends in precipitation in the Limpopo Province compared with the North West Province. Estimates of potential evapotranspiration and water balance indicated an increase in water demand while precipitation has remained the same or has decreased. The dramatic degree of mortality of E. ingens that has been observed since about 2000 appears to be linked to increasing moisture deficits resulting in tree stress, which in turn allows opportunistic fungal pathogens and insects to increase in severity, ultimately contributing to tree mortality.