Question Are plasma biomarkers associated with a return-to-sport period of less than 14 days vs 14 days or more in male and female collegiate athletes following a sport-related concussion? Findings This diagnostic study, which included 127 collegiate athletes who had sustained a sports-related concussion, found that higher total tau concentrations 24 to 48 hours after injury and at the time of symptom resolution as well as lower glial fibrillary acidic protein levels acutely postinjury were associated with return-to-sport decisions. Meaning In this study, total tau and glial fibrillary acidic protein levels were associated with return to sport in male and female collegiate athletes following a sports-related concussion. This diagnostic study examines whether plasma biomarkers can differentiate collegiate athletes who return to sport in less than 14 days vs 14 days or more following a sports-related concussion. Importance Identifying plasma biomarkers associated with the amount of time an athlete may need before they return to sport (RTS) following a sport-related concussion (SRC) is important because it may help to improve the health and safety of athletes. Objective To examine whether plasma biomarkers can differentiate collegiate athletes who RTS in less than 14 days or 14 days or more following SRC. Design, Setting, and Participants This multicenter prospective diagnostic study, conducted by the National Collegiate Athletics Association-Department of Defense Concussion Assessment, Research, and Education Consortium, included 127 male and female athletes who had sustained an SRC while enrolled at 6 Concussion Assessment, Research, and Education Consortium Advanced Research Core sites as well as 2 partial-Advanced Research Core military service academies. Data were collected between February 2015 and May 2018. Athletes with SRC completed clinical testing and blood collection at preseason (baseline), postinjury (0-21 hours), 24 to 48 hours postinjury, time of symptom resolution, and 7 days after unrestricted RTS. Main Outcomes and Measures A total of 3 plasma biomarkers (ie, total tau protein, glial fibrillary acidic protein [GFAP], and neurofilament light chain protein [Nf-L]) were measured using an ultrasensitive single molecule array technology and were included in the final analysis. RTS was examined between athletes who took less than 14 days vs those who took 14 days or more to RTS following SRC. Linear mixed models were used to identify significant interactions between period by RTS group. Area under the receiver operating characteristic curve analyses were conducted to examine whether these plasma biomarkers could discriminate between RTS groups. Results The 127 participants had a mean (SD) age of 18.9 (1.3) years, and 97 (76.4%) were men; 65 (51.2%) took less than 14 days to RTS, and 62 (48.8%) took 14 days or more to RTS. Linear mixed models identified significant associations for both mean (SE) plasma total tau (24-48 hours postinjury, <14 days RTS vs >= 14 days RTS: -0.65 [0.12] pg/mL vs -0.14 [0.14] pg/mL; P = .008) and GFAP (postinjury, 14 days RTS vs >= 14 days RTS: 4.72 [0.12] pg/mL vs 4.39 [0.11] pg/mL; P = .04). Total tau at the time of symptom resolution had acceptable discrimination power (area under the receiver operating characteristic curve, 0.75; 95% CI, 0.63-0.86; P < .001). We also examined a combined plasma biomarker panel that incorporated Nf-L, GFAP, and total tau at each period to discriminate RTS groups. Although the analyses did reach significance at each time period when combined, results indicated that they were poor at distinguishing the groups (area under the receiver operating characteristic curve, <0.7). Conclusions and Relevance The findings of this study suggest that measures of total tau and GFAP may identify athletes who will require more time to RTS. However, further research is needed to improve our ability to determine recovery following an SRC.