Abstract Regulation of ACE2, the SARS-CoV-2 receptor, could be important for susceptibility to COVID-19 or its outcomes. Here, we report the discovery of a transcriptionally independent truncated isoform of ACE2, designated as deltaACE2 (dACE2). dACE2 starts from a new exon in intron 9 of ACE2, and is highly conserved in primates. dACE2, but not ACE2, is induced by interferons and viruses including SARS-CoV-2. In-vitro, dACE2, which lacks 356 N-terminal amino acids, was non-functional in binding the SARS-CoV-2 spike protein and as a carboxypeptidase. Endogenous dACE2 protein appears to be unstable and poorly detectable. However, using our custom generated antibodies, we detected dACE2 in nasopharyngeal normal and tumor tissues by immunohistochemistry. In-vitro, overexpression of dACE2 inhibited SARS-CoV-2 infection, possibly by blocking internalization of the virus. Our results suggest that dACE2 might be an antiviral mechanism that evolved in primates to defend against certain viruses that utilize the ACE2 receptor for entry.