Background: Investigating future changes in temperature-related mortality as a function of global mean temperature (GMT) rise allows for the evaluation of policy-relevant climate change targets. So far, only few studies have taken this approach, and, in particular, no such assessments exist for Germany, the most populated country of Europe. Methods: We assess temperature-related mortality in 12 major German cities based on daily time-series of all-cause mortality and daily mean temperatures in the period 1993–2015, using distributed-lag non-linear models in a two-stage design. Resulting risk functions are applied to estimate excess mortality in terms of GMT rise relative to pre-industrial levels, assuming no change in demographics or population vulnerability. Results: In the observational period, cold contributes stronger to temperature-related mortality than heat, with overall attributable fractions of 5.49% (95%CI: 3.82–7.19) and 0.81% (95%CI: 0.72–0.89), respectively. Future projections indicate that this pattern could be reversed under progressing global warming, with heat-related mortality starting to exceed cold-related mortality at 3 °C or higher GMT rise. Across cities, projected net increases in total temperature-related mortality were 0.45% (95%CI: −0.02–1.06) at 3 °C, 1.53% (95%CI: 0.96–2.06) at 4 °C, and 2.88% (95%CI: 1.60–4.10) at 5 °C, compared to today's warming level of 1 °C. By contrast, no significant difference was found between projected total temperature-related mortality at 2 °C versus 1 °C of GMT rise. Conclusions: Our results can inform current adaptation policies aimed at buffering the health risks from increased heat exposure under climate change. They also allow for the evaluation of global mitigation efforts in terms of local health benefits in some of Germany's most populated cities. © 2020 The Authors