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Purpose of the Review: To evaluate the quality of evidence about the association of primary seizure prophylaxis with antiseizure medication (ASM) within 7 days postinjury and the 18- or 24-month epilepsy/late seizure risk or all-cause mortality in adults with new-onset traumatic brain injury (TBI), in addition to early seizure risk. Results: Twenty-three studies met the inclusion criteria (7 randomized and 16 nonrandomized studies). We analyzed 9,202 patients, including 4,390 in the exposed group and 4,812 in the unexposed group (894 in placebo and 3,918 in no ASM groups). There was a moderate to serious bias risk based on our assessment. Within the limitations of existing studies, our data revealed a lower risk for early seizures in the ASM prophylaxis group compared with placebo or no ASM prophylaxis (risk ratio [RR] 0.43, 95% confidence interval [CI] 0.33–0.57, p 0.00001, I2 = 3%). We identified high-quality evidence in favor of acute, short-term primary ASM use to prevent early seizures. Early ASM prophylaxis was not associated with a substantial difference in the 18- or 24-month risk of epilepsy/late seizures (RR 1.01, 95% CI 0.61–1.68, p = 0.96, I2 = 63%) or mortality (RR 1.16, 95% CI 0.89–1.51, p = 0.26, I2 = 0%). There was no evidence of strong publication bias for each main outcome. The overall quality of evidence was low and moderate for post-TBI epilepsy risk and all-cause mortality, respectively. Summary: Our data suggest that the evidence showing no association between early ASM use and 18- or 24-month epilepsy risk in adults with new-onset TBI was of low quality. The analysis indicated a moderate quality for the evidence showing no effect on all-cause mortality. Therefore, higher-quality evidence is needed as a supplement for stronger recommendations.