Background This study aimed to compare day-specific associations of blood-brain barrier (BBB) disruption with neurological outcome in survivors of out-of-hospital cardiac arrest (OHCA) treated with target temperature management (TTM) and lumbar drainage. Methods This retrospective single-center study included 68 survivors of OHCA who underwent TTM between April 2018 and December 2019. The albumin quotient (Q(A)) was calculated as Q(A) = albumin(cerebrospinal fluid)/albumin(serum) immediately (day 1) and 24 (day 2), 48 (day 3), and 72 h (day 4) after the return of spontaneous circulation. The degree of BBB disruption was weighted using the following scoring system: Q(A) value of 0.007 or less (normal), Q(A) value greater than 0.007-0.01 (mild), Q(A) value greater than 0.01-0.02 (moderate), and Q(A) value greater than 0.02 (severe). Points were assigned as follows: 0 (normal), 1 (mild), 4 (moderate), and 9 (severe). Neurological outcome was determined at 6 months after the return of spontaneous circulation, as well as cerebral performance category (CPC), dichotomized as good (CPC score 1-2) and poor (CPC score 3-5) outcome. Results We enrolled 68 patients (48 men, 71%); 37 (54%) patients had a poor neurological outcome. The distributions of poor versus good outcomes at 6 months in patients with moderate and severe BBB disruption were 19 of 22 (80%) vs. 18 of 46 (50%) on day 1, 31 of 37 (79%) vs. 6 of 31 (32%) on day 2, 32 of 37 (81%) vs. 5 of 31 (30%) on day 3, and 32 of 39 (85%) vs. 5 of 29 (30%) on day 4 (P < 0.001), respectively. Using receiver operating characteristic analyses, optimal cutoff values (sensitivity, specificity) of Q(A) levels for the prediction of neurological outcome were as follows: day 1, greater than 0.009 (56.8%, 87.1%); day 2, greater than 0.012 (81.1%, 87.1%); day 3, greater than 0.013 (83.8%, 87.1%); day 4, greater than 0.013 (86.5%, 87.1%); the sum of all time points, greater than 0.039 (89.5%, 79.4%); and scoring system, greater than 9 (91.9%, 87.1%). Conclusions In this proof of concept study, Q(A) was associated with poor neurological outcome in survivors of OHCA treated with TTM with no contraindication to lumbar drainage. A large multicenter prospective study is needed to validate the utility of BBB disruption as a prognosticator of neurological outcome.