Uranium was discovered in Karnes County, Texas, in 1954 and the first uranium mill began operating in 1961 near Falls City. Uranium milling and surface and in situ mining continued in Karnes County until the early 1990s. Remediation of uranium tailings ponds was completed in the 1990s. There were three mills and over 40 mines operating in Karnes County over these years and potential exposure to the population was from possible environmental releases into the air and ground water. From time to time concerns have been raised in Karnes County about potential increased cancer risk from these uranium mining and milling activities. To evaluate the possibility of increased cancer deaths associated with these uranium operations, a mortality survey was conducted. The numbers and rates of cancer deaths were determined for Karnes County and for comparison for four 'control' counties in the same region with similar age, race, urbanisation and socioeconomic distributions reported in the 1990 US Census. Comparisons were also made with US and Texas general population rates. Following similar methods to those used by the National Cancer Institute, standardised mortality ratios (SMRs) were computed as the ratio of observed numbers of cancers in the study and control counties compared to the expected number derived from general population rates for the United States. Relative risks (RRs) were computed as the ratios of the SMRs for the study and the control counties. Overall, 1223 cancer deaths occurred in the population residing in Karnes County from 1950 to 2001 compared with 1392 expected based on general population rates for the US. There were 3857 cancer deaths in the four control counties during the same 52 year period compared with 4389 expected. There was no difference between the total cancer mortality rates in Karnes County and those in the control counties (RR = 1.0; 95% confidence interval 0.9–1.1). There were no significant increases in Karnes County for any cancer when comparisons were made with either the US population, the State of Texas or the control counties. In particular, deaths due to cancers of the lung, bone, liver and kidney were not more frequent in Karnes County than in the control counties. These are the cancers of a priori interest given that uranium might be expected to concentrate more in these tissues than in others. Further, any radium intake would deposit primarily in the bone and radon progeny primarily in the lung. Deaths from all cancers combined also were not increased in Karnes County and the RRs of cancer mortality in Karnes County before and in the early years of operations (1950–64), shortly after the uranium activities began (1965–79) and in two later time periods (1980–89, 1990–2001) were similar, 1.0, 0.9, 1.1 and 1.0, respectively. No unusual patterns of cancer mortality could be seen in Karnes County over a period of 50 years, suggesting that the uranium mining and milling operations had not increased cancer rates among residents.