BACKGROUND AND OBJECTIVES: We present an illustrative case of spontaneous intracranial hypotension (SIH) in the setting of a suspected C1-2 cerebrospinal fluid (CSF) leak that was successfully treated with muscle, collagen, and epidural blood patch. We examined the literature to identify similar cases reporting Cl-2 retrospinal fluid collections identified on imaging in the setting of SIH and quantified the success of targeted treatment to this area despite previous reports that caution about a “C1-2 false localizing sign.” METHODS: A systematic search was performed identifying cases of SIH resulting from CSF leak with C1-2 fluid collection observed on imaging. PubMed, Google Scholar, and Web of Science were queried, and articles were screened for possible inclusion by 2 authors and supervised by the senior author. RESULTS: In total, 28 studies were included with a total of 32 patients. The number of patients in each study with C1-2 fluid collections, number of patients with fluid collections at multiple levels, specific intervention used, and outcomes of each intervention were recorded, with a focus on whether treatment occurred at the levels exhibiting fluid signal. CONCLUSION: Although the C1-2 fluid signal in SIH has previously been described as a “false localizing sign,” our study indicates that treating this level as the source of CSF leak results in successful and durable outcomes. Most SIH cases with signal at C1-2 did not have a fluid signal at any other level and were treated successfully and most commonly through epidural blood patch at the C1-2 level. Symptom resolution was also reported after direct repair of C1-2 CSF leaks through primary closure, Gelfoam patch, and muscle fragment with fibrin. In patients with SIH, C1-2 fluid signal, and no other source of CSF leak identified on imaging, surgical intervention at the C1-2 level seemed to have a high success rate.