Background Excessive summer heat is a serious environmental health problem in several European cities. Heat-related mortality and morbidity is likely to increase under climate change scenarios without adequate prevention based on locally relevant evidence. Methods We modelled the urban climate of Antwerp for the summer season during the period 1986–2015, and projected summer daily temperatures for two periods, one in the near (2026–2045) and one in the far future (2081–2100), under the Representative Concentration Pathway (RCP) 8.5. We then analysed the relationship between temperature and mortality, as well as with hospital admissions for the period 2009–2013, and estimated the projected mortality in the near future and far future periods under changing climate and population, assuming alternatively no acclimatization and acclimatization based on a constant threshold percentile temperature. Results During the sample period 2009–2013 we observed an increase in daily mortality from a maximum daily temperature of 26 °C, or the 89th percentile of the maximum daily temperature series. The annual average heat-related mortality in this period was 13.4 persons (95% CI: 3.8–23.4). No effect of heat was observed in the case of hospital admissions due to cardiorespiratory causes. Under a no acclimatization scenario, annual average heat-related mortality is multiplied by a factor of 1.7 in the near future (24.1 deaths/year CI 95%: 6.78–41.94) and by a factor of 4.5 in the far future (60.38 deaths/year CI 95%: 17.00–105.11). Under a heat acclimatization scenario, mortality does not increase significantly in the near or in the far future. Conclusion These results highlight the importance of a long-term perspective in the public health prevention of heat exposure, particularly in the context of a changing climate, and the calibration of existing prevention activities in light of locally relevant evidence.