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Silica exposure has been associated with kidney disease and rheumatoid arthritis; an autoimmune mechanism has been proposed. Approximately 2 million people are occupationally exposed to silica in the United States, 100,000 at more than twice the National Institute for Occupational Safety and Health recommended exposure limit of 0.05 mg/m3. We examined renal disease morbidity and mortality, as well as arthritis mortality, in a cohort of 4,626 silica-exposed workers in the industrial sand industry (an industry previously unstudied). We compared the cohort with the U.S. population and also conducted internal exposure-response analyses using a job-exposure matrix based on more than 4,000 industrial hygiene samples. We found excess mortality from acute renal disease [standardized mortality ratio (SMR) = 2.61, 95% confidence intervals (95% CIs) = 1.49–4.24; 16 deaths], chronic renal disease (SMR = 1.61, 95% CI = 1.13–2.22; 36 deaths), and arthritis (SMR = 4.36, 95% CI = 2.76–6.54; 23 deaths) on the basis of multiple-cause mortality data, which considered any mention of disease on a death certificate. Linking the cohort with the U.S. registry of end-stage renal disease for the years 1977–1996, we found an excess of end-stage renal disease incidence (standardized incidence ratio = 1.97, 95% CI = 1.25–2.96; 23 cases), which was highest for glomerulonephritis (standardized incidence ratio = 3.85, 95% CI = 1.55–7.93; 7 cases). We found increasing end-stage renal disease incidence with increasing cumulative exposure; standardized rate ratios by quartile of cumulative exposure were 1.00, 3.09, 5.22, and 7.79. A positive exposure-response trend was also observed for rheumatoid arthritis on the basis of death certificate data. These data represent the largest number of kidney disease cases analyzed to date in a cohort with well-defined silica exposure and suggest a causal link between silica and kidney disease. Excess risk of end-stage renal disease due to a lifetime of occupational exposure at currently recommended limits is estimated to be 14%, above a background end-stage renal disease risk of 2%.