Background: The high economic burden of cancer is projected to continue growing. Cost-of-care estimates are key inputs for comparative effectiveness and economic analyses that aim to inform policies associated with cancer care. Existing estimates are based largely on SEER-Medicare data in the elderly, leaving a knowledge gap regarding costs for patients aged <65 years. Methods: We estimated total and net medical care costs using data on individuals diagnosed with breast, colorectal, lung, or prostate cancer (n=45,522) and noncancer controls (n=314,887) enrolled in 1 of 4 participating health plans. Net costs were defined as the difference in mean total costs between patients with cancer and controls. The phase-of-care approach and Kaplan-Meier Sample Average method were used to estimate mean total and net 1- and 5-year costs (in 2015 US dollars) by cancer site, stage at diagnosis, and age group (<65 and ≥65 years). Results: Total and net costs were consistently highest for lung cancer and lowest for prostate cancer. Net costs were higher across all cancer sites for patients aged <65 years than those aged ≥65 years. Medical care costs for all cancers increased with advanced stage at diagnosis. Conclusions: This study improves understanding of medical care costs for the 4 most common invasive cancers in the United States. Higher costs among patients aged <65 years highlight limitations of relying on SEER-Medicare data alone to understand the national burden of cancer, whereas higher costs for patients with advanced-stage cancer underscore the importance of early detection to curtail high long-term costs. These cost estimates can be used in the development and evaluation of interventions and policies across the cancer care continuum.