PURPOSE: To systematically review studies that examined the influence of the CYP1A2 -163C>A polymorphism on the ergogenic effects of caffeine and to discuss some of the reasons for the discrepancies in findings between the studies. METHODS: This review was performed in accordance with the PRISMA guidelines. The search for studies was performed through nine databases. RESULTS: Seventeen studies were included in the review. Based on the included studies, it seems that individuals with the AA or AC/CC genotype may experience an increase in performance following caffeine ingestion. Significant differences between genotypes were found in four studies, and all four reported a more favorable response in the AA vs. AC/CC genotype. These results suggest that if there is an actual genotype-related effect of acute caffeine supplementation, it might be in that direction. In the studies that reported such data for aerobic endurance, the findings are specific to male participants performing cycling time trials (distances of ≥ 10 km) and ingesting caffeine 60 min before exercise. For high-intensity exercise, two studies reported that genotype variations determined the response to caffeine ingestion, even though the differences were either small (~ 1 additional repetition in high-load resistance exercise set performed to muscular failure) or inconsistent (i.e., observed only in one out of eight performance tests). CONCLUSIONS: CYP1A2 genotype variations may modulate caffeine's ergogenic effects, but the differences between genotypes were small, inconsistent, or limited to specific exercise scenarios. Future studies with larger sample sizes are needed to fully elucidate this research area.