Transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from humans to farmed mink has been observed in Europe and the US. In the infected animals, viral variants arose that harbored mutations in the spike (S) protein, the target of neutralizing antibodies, and these variants were transmitted back to humans. This raised concerns that mink might become a constant source of human infection with SARS-CoV-2 variants associated with an increased threat to human health and resulted in mass culling of mink. Here, we report that mutations frequently found in the S proteins of SARS-CoV-2 from mink are mostly compatible with efficient entry into human cells and its inhibition by soluble angiotensin-converting enzyme 2 (ACE2). In contrast, mutation Y453F reduces neutralization by an antibody with emergency use authorization for coronavirus disease 2019 (COVID-19) therapy and sera/plasma from COVID-19 patients. These results suggest that antibody responses induced upon infection or certain antibodies used for treatment might offer insufficient protection against SARS-CoV-2 variants from mink. Display omitted •SARS-CoV-2 from mink harbor up to five mutations in the spike protein•Entry inhibitors under clinical evaluation block mink spike proteins•Mutation Y453F confers partial escape from a therapeutic antibody•Y453F allows evasion of antibodies induced by SARS-CoV-2 infection of humans Transmission of SARS-CoV-2 between humans and farmed mink has caused concern because viruses from mink have acquired mutations in the spike protein. Hoffmann et al. show that these mink-specific mutations do not increase entry into human cells but do cause partial evasion from neutralization by a therapeutic antibody and convalescent plasma/sera.