Abstract Heat- and cold-related mortality risks are highly variable across different geographies, suggesting a differential distribution of vulnerability factors between and within countries, which could partly be driven by urban-to-rural disparities. Identifying these drivers of risk is crucial to characterize local vulnerability and design tailored public health interventions to improve adaptation of populations to climate change. We aimed to assess how heat- and cold-mortality risks change across urban, peri-urban and rural areas in Switzerland and to identify and compare the factors associated with increased vulnerability within and between different area typologies. We estimated the heat- and cold-related mortality association using the case time-series design and distributed lag non-linear models over daily mean temperature and all-cause mortality series between 1990–2017 in each municipality in Switzerland. Then, through multivariate meta-regression, we derived pooled heat and cold-mortality associations by typology (i.e. urban/rural/peri-urban) and assessed potential vulnerability factors among a wealth of demographic, socioeconomic, topographic, climatic, land use and other environmental data. Urban clusters reported larger pooled heat-related mortality risk (at 99th percentile, vs. temperature of minimum mortality (MMT)) (relative risk = 1.17 (95%CI: 1.10; 1.24), vs peri-urban 1.03 (1.00; 1.06), and rural 1.03 (0.99; 1.08)), but similar cold-mortality risk (at 1st percentile, vs. MMT) (1.35 (1.28; 1.43), vs rural 1.28 (1.14; 1.44) and peri-urban 1.39 (1.27–1.53)) clusters. We found different sets of vulnerability factors explaining the differential risk patterns across typologies. In urban clusters, mainly environmental factors (i.e. PM2.5) drove differences in heat-mortality association, while for peri-urban/rural clusters socio-economic variables were also important. For cold, socio-economic variables drove changes in vulnerability across all typologies, while environmental factors and ageing were other important drivers of larger vulnerability in peri-urban/rural clusters, with heterogeneity in the direction of the association. Our findings suggest that urban populations in Switzerland may be more vulnerable to heat, compared to rural locations, and different sets of vulnerability factors may drive these associations in each typology. Thus, future public health adaptation strategies should consider local and more tailored interventions rather than a one-size fits all approach.