A cohort mortality study of workers engaged in uranium milling and mining activities near Grants, New Mexico, during the period from 1955 to 1990 was conducted. Vital status was determined through 2005 and standardised mortality ratio (SMR) analyses were conducted for 2745 men and women alive after 1978 who were employed for at least six months. Overall, mortality from all causes (SMR 1.15; 95% CI 1.07–1.23; n = 818) and all cancers (SMR 1.22; 95% CI 1.07–1.38; n = 246) was greater than expected on the basis of US mortality rates. Increased mortality, however, was seen only among the 1735 underground uranium miners and was due to malignant (SMR 2.17; 95% CI 1.75–2.65; n = 95) and non-malignant (SMR 1.64; 95% CI 1.23–2.13; n = 55) respiratory diseases, cirrhosis of the liver (SMR 1.79; n = 18) and external causes (SMR 1.65; n = 58). The lung cancer excess likely is attributable to the historically high levels of radon in uranium mines of the Colorado Plateau, combined with the heavy use of tobacco products. No statistically significant elevation in any cause of death was seen among the 904 non-miners employed at the Grants uranium mill. Among 718 mill workers with the greatest potential for exposure to uranium ore, no statistically significant increase in any cause of death of a priori interest was seen, i.e., cancers of the lung, kidney, liver, or bone, lymphoma, non-malignant respiratory disease, renal disease or liver disease. Although the population studied was relatively small, the follow-up was long (up to 50 yrs) and complete. In contrast to miners exposed to radon and radon decay products, for uranium mill workers exposed to uranium dusts and mill products there was no clear evidence of uranium-related disease.