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BACKGROUND: Product safety assurance is crucial for the clinical use of manufactured cellular therapies. A rational approach for delivering products which fail release criteria (due to potentially false-positive sterility results) is important to avoid unwarranted wastage of highly personalized and costly therapies in critically ill patients where benefits may outweigh risk. Accurate and timely interpretation of microbial sterility assays represents a major challenge in cell therapies. METHODS: We developed a systematic protocol for the assessment of positive microbial sterility test results using retrospective data from 2007 to 2016. This protocol was validated and applied prospectively between October 2016 and September 2017 to 13 products from which positive sterility results had been reported. Viable and non-viable environmental monitoring (EM) data were collected concurrently as part of facility control assessment. RESULTS: Three of 13 (23%) positive sterility results were attributable to bone marrow collections that had been contaminated with skin flora during harvest; all were infused without pertinent infectious sequelae. Of the remaining 10, one was deemed a true positive and was discarded prior to infusion, while nine were classified as false positives attributed to laboratory sampling and/or culturing processes. Three products deemed false positive were infused and six were withheld due to patient issues unrelated to microbial sterility results. No post-infusion associated infectious complications were documented. Almost half of the positive EM findings were skin flora. Paired detection of an organism in both product and associated EM was identified in one case. CONCLUSION: Application of our validated protocol to positive product sterility test results allowed for systematic data compilation for regulatory evaluation and provided comprehensive information to clinical investigators to ensure timely and strategic management for product recipients.