Updating and evaluating facility-based guidance in cancer centers for managing healthcare personnel (HCP) with close contact with individuals with coronavirus disease 2019 (COVID-19) is challenging because these settings are typically excluded from general guidance, and practical data on this population are limited. This study aimed to describe whether apparent outbreaks occurred under the updated protocol in the real-world setting of a cancer center. From July 2022 to January 2023, 402 HCP who had close contact with an individual with COVID-19 were identified and divided into two groups: the separation group, which underwent a five-day quarantine with physical isolation (172 HCP), and the cohabitation group, which followed a ten-day quarantine (227 HCP). A nucleic acid amplification test (NAAT) was conducted the day before the HCP returned to work. Data from their medical records were retrospectively collected and analyzed. As a primary outcome, no outbreaks due to post-quarantine transmission from close-contacted HCP were observed throughout the study period in either group. Our findings suggested a 5-day quarantine for HCP with close contact with COVID-19 might be applicable in cancer center settings if combined with NAAT before returning to work without increasing the risk of apparent outbreaks.