BACKGROUND: The correlation between human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP) usage and sexually transmitted infections (STIs) remains equivocal. Limited studies have investigated national STI trends after introducing PrEP. We aimed to examine STI incidence before and after PrEP introduction and explore correlations with PrEP use in the United States. METHODS: PrEP usage data (2012-2022) were obtained from AIDSVu, and STI data (2001-2022) from the Centers for Disease Control and Prevention's STI Statistics Archive. We used the coefficient of determination to estimate variance in STI rates explained by PrEP usage. We used cross-correlation to identify lagged correlations and segmented linear regression to examine STI trends by demographics before and after PrEP initiation. RESULTS: Syphilis rates increased by 0.2/100 000 people annually before 2012 and by 1.4/100 000 persons after PrEP introduction. Gonorrhea rates dropped by 2.9/100 000 people before 2012 but rose by 14/100 000 afterward. The slope for chlamydia dropped from 20.9 to 6.6. The coefficients of determination for syphilis, gonorrhea, and chlamydia attributable to PrEP usage were 0.98, 0.88, and 0.2, respectively. Lagged correlations were significant for chlamydia, but not for syphilis and gonorrhea. Overall, STI rates were more strongly correlated with PrEP usage among males than females. CONCLUSIONS: We found significant changes in the rate of incident STIs from 2012 to 2022 and a high correlation between PrEP usage and reported cases of syphilis and gonorrhea. Given the role of PrEP in comprehensive HIV prevention in the United States, its impact on rates of STI infection should be further studied.