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BACKGROUND: Research on the acute effects of a concussion among lacrosse players is limited, and postconcussion patterns between male and female athletes have yet to be clearly established. Differences in the style of play and protective gear worn among male and female lacrosse players potentially confound a direct comparison of sex-based differences in this population. PURPOSE: To explore sex-based differences in postconcussive neurocognitive functioning and symptom reporting outcomes in concussed adolescent male and female lacrosse players compared with a group of soccer players. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A total of 224 adolescent lacrosse players (112 male, 112 female) aged 13 to 17 years (mean [+/-SD] age, 15.43 +/- 1.09 years) were included in this study. A comparison group of soccer players was added and matched to lacrosse players based on age and sex to address confounding sport differences in male and female versions of lacrosse. All athletes underwent baseline and postinjury testing within 3 days of an injury using the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) tool. Data were analyzed at baseline using a multivariate analysis of variance (MANOVA) with sport and sex as between-participant factors. A 2 x 2 x 2 mixed-factorial MANOVA was also conducted for sex and sport comparisons at baseline versus after a concussion. Ancillary analyses evaluated sex-based differences in exceeded reliable change indices (RCIs) using an independent-samples t test and established postinjury cutoff scores reflective of a protracted recovery using chi-square tests. RESULTS: All athletes had a significantly worse cognitive profile and greater endorsement of symptoms after an injury (F5,216 = 30.30, P < .001, etarho2 = .41). Sport yielded a significant main effect (F5,216 = 2.36, P = .04, etarho2 = .05), but subsequent univariate analyses were nonsignificant (P > .05) across all neurocognitive and symptom outcome variables. Likewise, there were no significant interaction effects for sport x time (F5,216 = 1.46, P = .21, etarho2 = .03) or sport x sex x time ( F5,216 = 2.09, P = .07, etarho2 = .05), indicating that lacrosse and soccer players respond similarly on neurocognitive testing and symptom reporting after sustaining a concussion. Regarding sex-based differences, female athletes had a significantly greater neurocognitive decline and increased symptoms after a concussion relative to male athletes, regardless of the sport type (sex x time interaction effect: F5,216 = 3.86, P = .002, etarho2 = .08), with the relationship between concussions and sex demonstrating a medium- to large-sized effect. Female athletes demonstrated a significantly greater number of exceeded RCIs ( t(216.16) = -3.732, P < .001), with 59% of male and 74% of female athletes with at least 1 RCI decline. Approximately 13% of male athletes, compared with 30% of female athletes, demonstrated scores indicative of protracted recovery at a 75% sensitivity (chi2 (1, N = 224) = 9.43, P = .002). CONCLUSION: Athletes performed more poorly on computerized cognitive screening tools and reported greater symptoms after an acute concussion relative to their baseline performance. Female sex may be a modifier of an acute concussion outcome, given that female athletes in this study performed significantly worse than male athletes across all neurocognitive measures and reported greater symptoms relative to their baseline testing compared with male athletes, regardless of the sport played. Female athletes were also more likely than male athletes to demonstrate scores on neurocognitive testing that exceeded reliable change cutoffs and were predictive of a protracted recovery. The practical significance of these findings should be further verified by prospective longitudinal research given the medium- to large-sized effect demonstrated for the overall relationship between sex and concussions.