The coronavirus disease 2019 (COVID-19) outbreak started in December 2019 and rapidly spread around the globe as a major health threat. Several reports on re-positive cases subsequent to discharge from hospitals caught our attention. We aimed to highlight RT-qPCR positivity re-detection after discharge from isolation, with special consideration of the possible reasons behind it. We found that re-positive RT-qPCR assays for severe acute respiratory syndrome coronavirus 2 after previous negative results might be attributed to false-negative laboratory results and prolonged viral shedding, rather than to re-infection. These findings are encouraging and should be validated in a larger cohort.