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<b>Background.</b> Interferon is a marker of host antiviral immunity, which is disordered in COVID-19 patients. ERV can affect the secretion of interferon through the cGAS-STING pathway. In this study, we explored whether IFN-I and HERV-K (HML-2) were activated in COVID-19 patients and whether there was an interaction between them. <b>Methods.</b> We collected blood samples from COVID-19 patients and healthy controls. We first detected the expression of HERV-K (HML-2) <i>gag</i>, <i>env</i>, and <i>pol</i> genes and IFN-I-related genes between patients and healthy people by qPCR, synchronously detected VERO cells infected with SARS-CoV-2. Then, the chromosome distributions of highly expressed HERV-K (HML-2) <i>gag</i>, <i>env</i>, and <i>pol</i> genes were mapped by the next-generation sequencing results, and GO analysis was performed on the related genes. <b>Results.</b> We found that the HERV-K (HML-2) <i>gag</i>, <i>env</i>, and <i>pol</i> genes were highly expressed in COVID-19 patients and VERO cells infected with SARS-CoV-2. The interferon-related genes <i>IFNB1</i>, <i>ISG15,</i> and <i>IFIT1</i> were also activated in COVID-19 patients, and GO analysis showed that HERV-K (HML-2) can regulate the secretion of interferon. <b>Conclusions.</b> The high expression of HERV-K (HML-2) might activate the increase of interferon in COVID-19 patients, proving that HERV-K does not only play a negative role in the human body.