Colorectal cancer (CRC) remains the third most common cancer and cancer-related death in US women and men. Although the totality of evidence in aggregate supports a beneficial role of calcium in colorectal carcinogenesis, three major unresolved outstanding questions exist. First, the optimal dose and timing of calcium intake for CRC prevention remains unknown. Second, although several proposed mechanisms for calcium's role in risk may also influence cancer progression, no study has yet examined whether post-diagnostic calcium intake will improve survival among CRC patients. Lastly, the biological pathways by which calcium influences CRC risk remain unknown. Because future randomized controlled trials may not be feasible to test different doses with long or unknown latency between start intervention and CRC onset, we propose to examine the following specific aims using the resources of two large, well- characterized cohorts of women (the Nurses' Health Study, NHS) and men (the Health Professionals Follow-up Study, HPFS), in which calcium intake was assessed every 4 years since 1980 and 1986 respectively, using validated food frequency questionnaires. With up to 3 decades of follow-up, long-term effects can be studied. Aim 1 is to investigate the optimal dose and timing of calcium intake for CRC prevention. Aim 2 is to assess whether adequate post- diagnostic calcium intake is associated with better CRC survival. Aim 3 is to discover biological pathways through which calcium might operate to reduce risk of CRC using pre-existing mRNA expression data from the CRC tumors. Two large cohort studies of women and men with multiple calcium assessments and pre-existing validated mRNA expression data provide a unique opportunity to address the proposed aims in a cost-effective manner. Completion of this project will make important contributions towards informing future dietary recommendations of calcium intake for CRC prevention and survival in US adults.