BACKGROUND: Athletic performance is a complex phenotype affected by individual traits, environmental conditions, training, and genetics. The peroxisome proliferator-activated receptor-alpha (PPARα) and alpha-actinin-3 (ACTN3) are two genes with the potential to influence human performance. The objective of the present study was to assess the genotype frequencies of ACTN3 (R/X) and PPARα (G/C) and to conduct a comparison of these frequencies among Egyptian adolescent athletes. METHODS: This case-control study involved 228 individuals (118 elite-level athletes and 110 sedentary controls). RESULTS: This study identified a statistically significant increase in the frequencies of the ACTN3 'R' allele (77.5% compared to 55.9%; p < 0.001) and the PPARα 'C' allele (86.4% compared to 14.1%; p < 0.001) among athletes relative to the control groups. A similar pattern was noted for adolescent athletes in comparison to the control group in terms of both the R/R genotype (61.9% compared to 27.3%; p < 0.001) and the C/C genotype (80.5% compared to 2.7%; p < 0.001). In conclusion, these results imply that polymorphisms in ACTN3 and PPARα could be significant predictors for assessing the performance of adolescent Egyptian athletes.