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The reindeer herding Sami of Sweden have low incidences of cancer. The aim of the present study was to investigate the cancer risk in a large cohort of Swedish Sami, containing Sami with different lifestyle and genetic Sami heritage. A cohort of 41,721 Sami identified in official national registers between 1960 and 1997, was divided into two sub-populations - reindeer herding Sami (RS) and non-reindeer herding Sami (NRS). A demographically matched non-Sami reference population (NS) was used as standard when incidence and mortality ratios were calculated. Incidence and mortality data were obtained from the Swedish Cancer and Cause of Death Registers for the period 1961–2003. For Sami men, lower risks were found for cancers of the colon and prostate, and for malignant melanoma and non-Hodkins lymphoma, but higher for stomach cancer. The Sami women showed higher risks for cancers of the stomach and the ovaries, but lower risk for cancer of the bladder. The RS demonstrated lower relative cancer risks compared with the NRS. The lowest relative risk was found among the RS men, while the highest were observed among the NRS women. The RS men who had adopted a more westernized lifestyle showed a similar relative risk for prostate cancer as that of the NS living in the same region. Most of these differences in cancer risks could probably be ascribed to differences in lifestyle. It is concluded that the traditional Sami lifestyle contains elements, e.g. dietary contents and physical activity that may protect them from developing cancer.