Despite the relevance of road crashes and their impact on social and health care costs, the effects of extreme temperatures on road crashes risk have been scarcely investigated, particularly for those occurring in occupational activities. A nationwide epidemiological study was carried out to estimate the risk of general indistinct and work-related road crashes related with extreme temperatures and to identify crash and occupation parameters mostly involved. Data about road crashes, resulting in death or injury, occurring during years 2013–2015 in Italy, were collected from the National Institute of Statistics, for general indistinct road crashes, and from the compensation claim applications registered by the national workers' compensation authority, for work-related ones. Time series of hourly temperature were derived from the results provided by the meteorological model WRF applied at a national domain with 5 km resolution. To consider the different spatial-temporal characteristics of the two road crashes archives, the association with extreme temperatures was estimated by means of a case-crossover time-stratified approach using conditional logistic regression analysis, and a time-series analysis, using over-dispersed Poisson generalized linear regression model, for general indistinct and work-related datasets respectively. The analyses were controlled for other covariates and confounding variables (including precipitation). Non-linearity and lag effects were considered by using a distributed lag non-linear model. Relative risks were calculated for increment from 75th to 99th percentiles (hot) and from 25 to first percentile (cold) of temperature. Results for general indistinct crashes show a positive association with hot temperature (RR = 1.12, 95 % CI: 1.09–1.16) and a negative one for cold (RR = 0.93, 95 % CI: 0.91−0.96), while for work-related crashes a positive association was found for both hot and cold (RR = 1.06 (95 % CI: 1.01–1.11) and RR = 1.10 (95 % CI: 1.05–1.16). The use of motorcycles, the location of accident (urban vs out of town), presence of crossroads, as well as occupational factors like the use of a vehicle on duty were all found to produce higher risks of road crashes during extreme temperatures. Mitigation and prevention measures are needed to limit social and health care costs.