OBJECTIVES: (1) To perform a systematic literature review to evaluate associations between post-dural puncture headache (PDPH) and opening pressure (OP), closing pressure (CP), and volume of cerebrospinal fluid (V) removed. (2) To perform a case-control study to evaluate pressure-volume index (PVI) as a novel risk factor for PDPH. BACKGROUND: According to the International Classification of Headache Diagnoses, 3rd Edition (ICHD-3), the diagnosis of PDPH requires documentation of intracranial hypotension. However, this remains an unproven concept. METHODS: A systematic literature review was conducted, searching Cochrane Database of Systematic Reviews, Ovid EMBASE, OVID MEDLINE, Scopus, and Web of Science. Study inclusion required a comparison of headache incidence following a LP as a function of OP, CP, and/or V. A retrospective, case-control study with 1:1 matching was conducted utilizing ICHD-3 criteria. Patients with factors that could influence CSF pressure were excluded. RESULTS: In our case-control study, we did not identify a paired difference in either median (95% CI) elastance (0.05 [-0.09, 0.11], P = .503) or PVI (4.53 [-7.98, 19.97], P = .678). We identified 22 references, evaluating V (n = 14), OP (n = 11), and/or CP (n = 4). There was no convincing evidence for an association of PDPH with either OP or CP. A minority of studies documenting an association with V included patients with high-volume CSF removal, and/or stratified patients by the timing of the headache onset. CONCLUSIONS: The overall risk of PDPH does not appear to be influenced by OP, CP, V or PVI. PDPH may be related to V in instances of high-volume removal, and depend on the timing of outcome assessment. Future revision of criteria should consider the existence of immediate and delayed PDPH subtypes, and not presume intracranial hypotension as a mandatory feature.