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Low back pain has a high prevalence and morbidity, and is a source of substantial health-care spending. Numerous published guidelines support the use of so-called red flag questions to screen for serious pathology in patients with low back pain. This paper examines the effectiveness of red flag questions as a screening tool for patients presenting with low back pain to a multidisciplinary academic spine center.We conducted a retrospective review of the cases of 9,940 patients with a chief complaint of low back pain. The patients completed a questionnaire that included several red flag questions during their first physician visit. Diagnostic data for the same clinical episode were collected from medical records and were corroborated with imaging reports. Patients who were diagnosed as having a vertebral fracture, malignancy, infection, or cauda equina syndrome were classified as having a red flag diagnosis.Specific individual red flags and combinations of red flags were associated with an increased probability of underlying serious spinal pathology, e.g., recent trauma and an age of >50 years were associated with vertebral fracture. The presence or absence of other red flags, such as night pain, was unrelated to any particular diagnosis. For instance, for patients with no recent history of infection and no fever, chills, or sweating, the presence of night pain was a false-positive finding for infection >96% of the time. In general, the absence of red flag responses did not meaningfully decrease the likelihood of a red flag diagnosis; 64% of patients with spinal malignancy had no associated red flags.While a positive response to a red flag question may indicate the presence of serious disease, a negative response to 1 or 2 red flag questions does not meaningfully decrease the likelihood of a red flag diagnosis. Clinicians should use caution when utilizing red flag questions as screening tools.