A subset of patients with coronavirus disease-2019 (COVID-19) develop cutaneous manifestations of their severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, including pernio of their feet and hands, known as “COVID toes.” These patients tend to have a mild disease course, which may indicate successful viral control by the host. By leveraging an existing patient cohort at Massachusetts General Hospital (MGH), and the extensive laboratory infrastructure at the NIH, this proposal aims to elucidate the complex determinants of a unique phenotype of COVID-19: pernio/ “COVID toes,” with the following Aims. Aim 1: To evaluate genetic determinants of pernio-like lesions (“COVID toes”) in response to SARS-CoV-2 infection. Aim 2: To characterize the inflammatory and serological response during acute infection and convalescence of patients with SARS-CoV-2 who develop pernio-like lesions as a symptom of COVID-19. Biological samples will be obtained at MGH and sent to collaborating labs at the NIH. In particular, this proposal will help us understand the host immune response to COVID-19 by focusing on patients who have controlled the disease and have had relatively mild clinical courses, as characterized by their skin lesions. Successful completion of our aims will immediately and directly respond to important gaps in our knowledge regarding mild/asymptomatic COVID-19, which in turn can help inform our understanding of how to harness this type of successful control for other patients.