The circumstances of homelessness create the potential for rapid transmission of SARS-CoV-2 in this vulnerable population. Upon observing a cluster of COVID-19 cases from a single large homeless shelter in Boston, Boston Health Care for the Homeless Program conducted symptom assessments and polymerase chain reaction (PCR) testing for SARS-CoV-2 among all guests residing at the shelter over a 2-day period. Of 408 participants, 147 (36.0%) were PCR-positive for SARS-CoV-2. COVID-positive individuals were more likely to be male (p<0.001) but did not differ significantly from COVID-negative individuals with respect to other demographic and clinical characteristics. Cough (7.5%), shortness of breath (1.4%), and fever (0.7%) were all uncommon among COVID-positive individuals. Our findings illustrate the rapidity with which COVID-19 can be widely transmitted in a homeless shelter setting and suggest that universal PCR testing, rather than a symptom triggered approach, may be a better strategy for identifying and mitigating…