Kidney cancer is the 7th leading malignant condition among men and the 9th among women, accounting for 4% of all cancers. The majority of kidney cancer is renal cell cancer (RCC), with the remainder of cases mostly renal pelvis cancer. The incidence of kidney cancer has been rising in the U.S. and worldwide. Nevertheless, the etiology of this malignancy is largely unexplored. Analgesics are a diverse group of drugs used to relieve pain, including acetaminophen and non-steroidal anti- inflammatory drugs (NSAIDs). The NSAID aspirin is one of the most commonly used drugs in the U.S. and is well-known for its protective effect against cardiovascular disease and colorectal cancer. Aspirin may reduce kidney cancer by reducing inflammation, inhibiting cycloxygenase-2, inhibiting cell proliferation, and inducing apoptosis of cancer cells. However, limited epidemiologic data are available, with few prospective data for analgesic use and kidney cancer risk. Furthermore, previous case-control studies on analgesic use and kidney cancer risk point toward a positive association. In fact, some analgesics such as acetaminophen may contribute to decline of renal function and elevated risk of chronic renal disease and, subsequently, to elevated risk of kidney cancer. Thus, given the popularity of aspirin and other analgesics, clarification of the association is necessary from a public health standpoint. In this application, we will determine the effects of individual and total analgesic use on the risk of kidney cancer. We hypothesize that use of aspirin and other NSAIDs is associated with a reduced risk of kidney cancer, but that use of acetaminophen is associated with an elevated risk of kidney cancer. We will evaluate these hypotheses using two different study designs;1) in large prospective studies of male and female with 430 kidney cancer cases (350 RCC) and 2) in a meta-analysis of previous literature including both case-control and cohort studies with over 5,600 kidney cancer cases. These two study designs will complement the strength of each study design. We believe that this proposed work will provide the best available data on analgesic use and kidney cancer risk and substantially enhance our understanding of the role of analgesics in renal carcinogenesis. Our findings will provide insights into the biological mechanisms potentially underlying these associations. Because of the popularity of aspirin and other analgesics, this proposed work has substantial public health implications.