Melanoma incidence in the United States has increased 15-fold over the last 70 years.  Despite prevention efforts targeting sun exposure, the major risk factor for melanoma, the mortality from this disease continues to rise.  Therefore, other approaches such as chemoprevention have emerged as areas of investigation.  One promising class of medications, non-steroidal anti-inflammatory drugs (NSAIDs), has demonstrated protective effects against melanoma in cell lines and mouse models.  We have recently conducted a case-control study in humans that found that subjects taking non-aspirin NSAIDs had a 40% decreased risk of melanoma compared to those who did not take these medications.  Based on these results, we propose a study dedicated to investigating our hypothesis that regular use of NSAIDs has a chemoprotective effect against melanoma.  We will evaluate this hypothesis by pooling data from the Nurses Health Study and the Health Professionals Follow-up Study to address three specific aims: (1) To confirm our preliminary finding of an inverse relationship between the use of NSAIDs and risk of invasive melanoma; (2) To determine the effects of NSAIDs on risk of melanoma in situ, and (3) To assess the influence of NSAIDs on melanoma invasion, as measured by tumor Breslow depth and growth phase.  By pooling these studies, effects can be determined in both men and women, and power is increased for more precise estimates of effect.  Through our analysis of existing data from these studies, we hope to identify an agent for clinical chemoprevention trials.  Due to the large numbers of individuals taking NSAIDs and the increasing incidence of melanoma, we believe that the detection of an effect will make a significant contribution to the public health.  This study proposes to investigate whether regular use of non-steroidal anti-inflammatory drugs (NSAIDs) may protect individuals against melanoma.  This question will be addressed using data from the Nurses Health Study and the Health Professionals Follow-up Study, two large groups of health professionals who have provided information about their health for up to 24 years.  Due to the large numbers of individuals taking NSAIDs and the increasing incidence of melanoma, we believe that the detection of an effect will make a significant contribution to the public health. [ unreadable] [unreadable] [unreadable]