The eastern Mediterranean region is characterized by rising temperature trends exceeding the corresponding global averages and is considered a climate change hot-spot. Although previous studies have thoroughly investigated the impact of extreme heat and cold on human mortality and morbidity, both for the current and future climate change scenarios, the temporal trends in temperature-related mortality or the potential historical adaptation to heat and cold extremes has never been studied in this region. This study focuses on cardiovascular mortality and assesses the temporal evolution of the Minimum Mortality Temperature (MMT), as well as the disease-specific cold- and heat-attributable fraction of mortality in three typical eastern Mediterranean environments (Athens, Thessaloniki and Cyprus). Data on daily cardiovascular mortality (ICD-10 code: I00–I99) and meteorological parameters were available between 1999 and 2019 for Athens, 1999 to 2018 for Thessaloniki and 2004 to 2019 for Cyprus. Estimation of cardiovascular MMT and mortality fractions relied on time-series Poisson regressions with distributed lag nonlinear models (DLNM) controlling for seasonal and long-term trends, performed over a series of rolling sub-periods at each site. The results indicated that in Athens, the MMT decreased from 23 °C (67.5th percentile) in 1999–2007 to 21.8 °C (62nd percentile) in 2011–2019, while in Cyprus the MMT decreased from 26.3 °C (79th percentile) in 2004–2012 to 23.9 °C (66.5th percentile) in 2011–2019. In Thessaloniki, the decrease in MMT was rather negligible. In all regions under study, the fractions of mortality attributed to both cold and heat followed an upward trend throughout the years. In conclusion, the demonstrated increase in cold attributable fraction and the decreasing temporal trend of MMT across the examined sites are suggestive of maladaptation to extreme temperatures in regions with warm climate and highlight the need for relevant public health policies and interventions. Display omitted •Adaptation to heat and cold has never been investigated in Eastern Mediterranean.•We assessed temporal trends in temperature-related CVD mortality in three sites.•Evidence of a decreasing temporal trend was observed for Minimum Mortality Temperature.•Across all sites, cold-attributable fraction of CVD mortality increased.•Results are suggestive of maladaptation to temperature extremes in warm environments.