© 2020, Springer Science+Business Media, LLC, part of Springer Nature. Purpose: The influenza vaccine is essential in reducing the influenza burden, especially among healthcare workers (HCW). Experimental studies suggest both coronaviruses and influenza viruses engage with the angiotensin-converting enzyme 2 (ACE 2) and tetraspanin antibodies, and that ACE 2 tetraspanin antibodies in turn may inhibit both coronavirus and low-pathogenicity influenza A viruses (LP IAV) infections. This study aims to investigate the potential clinical association between receiving the 2019 influenza vaccine and the incidence of COVID-19 among HCW. Methods: We designed a case–control study within a hospital setting in Iran when it became a center for treating COVID-19 patients. We collected data and calculated relevant incidence and associative measures among HCW who had received the 2019 influenza vaccine as compared to HCW who had not received the vaccine. Results: Our total sample size was 261 HCW. Of 80 COVID-19 incident cases, three cases had received the influenza vaccine, while 87 of 181 controls had received the vaccine. The odds ratio (OR) and confidence interval (CI) of being vaccinated were 0.04 (95% CI: 0.01 to 0.14) among COVID-19 cases as compared to controls. Conclusions: Significant findings suggest that the 2019 influenza vaccine may have a protective association against COVID-19 among HCW.