Background: Cerebrovascular reactivity is an important contributor to secondary injury following traumatic brain injury (TBI). The poor spatial resolution and invasive nature of “Gold-standard” intracranial pressure (ICP) based indies of cerebrovascular reactivity limit their use. Near infrared spectroscopy (NIRS) based indices of cerebrovascular reactivity are minimally invasive and have improved spatial resolution. The precise relationship between NIRS and ICP based indices is quantified utilizing times series analysis and advanced statistical techniques. Methods: High-resolution physiologic data was collected in a cohort of adult moderate to severe TBI patients at a single quaternary care site. From this data both ICP and NIRS based indices of cerebrovascular reactivity were derived. The times series structure of these indices was determined and used to correct for autocorrelation in a linear mixed effects model of ICP based indices from NIRS based indices of cerebrovascular reactivity. Results: A total of 83 patients were included in this study. Times series analysis coupled with mixed effects modeling was utilized to examine the relationship between ICP and NIRS based indices of cerebrovascular reactivity. Conclusions: Times series analysis coupled with mixed effects modeling allows for a more complete understanding of the relationship between ICP and NIRS based indices of cerebrovascular reactivity in the setting TBI.