Background: The efficient transmission of Severe Acute Respiratory Syndrome-2 Coronavirus (SARS-CoV-2) from patients to healthcare workers or family members has been a worrisome and prominent feature of the ongoing outbreak. On the basis of clinical practice and in-vitro studies, we postulated that post-exposure prophylaxis (PEP) using Arbidol is associated with decreased infection among individuals exposed to confirmed cases of COVID-19 infection. Methods: We conducted a retrospective case-control study on family members and health care workers who were exposed to patients confirmed to have SARS-CoV-2 infection by real-time RT-PCR and Chest CT from January 1 to January 16, 2020. We collected demographic information, work location of exposure, post-exposure prophylaxis information, and symptoms, if any, 24 days after exposure. The relation between post-exposure prophylaxis and infection in household contacts and healthcare workers were respectively analyzed. Results: 27 families and 124 health care workers had evidence of close exposure to patients with confirmed COVID-19. There were no differences in age, profession and sex distribution in the two groups with different post-exposure prophylaxis, table 1. Logistic regression based on the data of the family members and health care workers with Arbidol or Oseltamivir prophylaxis showed that Arbidol PEP was a strong protective factor against the development of COVID-19 (Odds ratio 0·011 , 95% CI 0·001-0·125, P=0·0003 for family members and Odds ratio 0·049, 95%CI 0·003-0·717), P= 0·0276 for health care workers). On the contrary, Oseltamivir was associated with an increase in COVID-19 infection (Odds ratio 20·446, 95% CI 1·407-297·143, P= 0·0271). Conclusions: Our findings suggest Arbidol could reduce the infection risk of the novel coronavirus in hospital and family settings. This treatment should be promoted for PEP use and should be the subject of further investigation.