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Clinicians do not want to miss underlying serious pathology, but it is still unclear which red flags are relevant. We aimed to evaluate the origin and evidence on diagnostic accuracy of red flags for malignancy for management of low back pain (LBP) in primary care. We performed a comprehensive overview and searched the literature using snowballing techniques and reference checking for evidence on red flags endorsed in clinical guidelines for identifying patients with higher likelihood of malignancy. We selected studies including people with LBP without any restriction on study design. We extracted data on prevalence and diagnostic accuracy. Furthermore, we assessed the methodological quality of studies evaluating diagnostic accuracy. We identified 13 red flags endorsed in a total of 16 guidelines and 2 extra red flags not endorsed in any guideline. We included 33 publications varying from systematic reviews to case reports. The origin of many red flags was unclear or was sourced from case reports. The incidence of malignancy in patients presenting with LBP in primary care varied between 0% and 0.7%. Seven studies provided diagnostic accuracy data on red flags. We found 5 red flags with accuracy data from 2 or more studies, with 2 (“history of malignancy” and “strong clinical suspicion”) considered informative. In conclusion, the origin and diagnostic accuracy of many red flags endorsed in guidelines are unclear. A “history of malignancy” and “strong clinical suspicion” are the only red flags with empirical evidence of acceptably high diagnostic accuracy.