Abstract Background Initial CDC recommendations for passive monitoring of COVID-19 related symptoms among staff may not be sufficient in preventing the introduction and transmission of SARS-CoV-2 in healthcare settings. We therefore implemented active monitoring for SARS-CoV-2 infection in healthcare workers (HCWs) at an academic medical center during the COVID-19 epidemic in northeast US. Methods We recruited a cohort of HCWs at Yale New Haven Hospital who worked in COVID-19 units and did not have COVID-19 related symptoms between March 28 and June 1, 2020. During follow-up, participants provided daily information on symptoms by responding to a web-based questionnaire, self-administered nasopharyngeal (NP) and saliva specimens every 3 days, and blood specimens every 14 days. We performed SARS-CoV-2 RT-PCR and an anti-spike protein IgM and IgG ELISA to identify virological and serological-confirmed infection, respectively. Results We enrolled 525 (13%) amongst 4,136 HCW of whom daily information on symptoms and NP, saliva, and blood specimens were obtained for 66% (of 13208), 42% (or 1977), 44% (of 2071) and 65% (of 1099), respectively, of the follow-up measurement points. We identified 16 (3.0% of 525) HCWs with PCR-confirmed SARS-CoV-2 infection and an additional 12 (2.3% of 525) who were not tested by PCR or had negative PCR results but had serological evidence of infection. The overall cumulative incidence of SARS-CoV-2 infection was 5.3% (28 of 525) amongst HCWs. Cases were not identified by hospital protocols for passive staff self-monitoring for symptoms. Amongst 16 PCR-confirmed cases, 9 (56%) of the 16 PCR-confirmed HCW had symptoms during or after the date of initial detection. We did not identify an epidemiological link between the 28 confirmed cases. Conclusion We found that a significant proportion (5.3%) of HCWs were infected with SARS-CoV-2 during the COVID-19 epidemic. In the setting of universal PPE use, infections were possibly acquired in the community rather than stemming from patient-HCW or HCW-HCW transmission. Passive monitoring of symptoms is inadequate in preventing introductions of SARS-CoV-2 into the healthcare setting due to asymptomatic and oligosymptomatic presentations. Disclosures All Authors: No reported disclosures