OBJECTIVES: STIs cause inflammation that is detrimental for both HIV risk and reproductive health. We assessed the impact of point-of-care (POC) STI testing, immediate treatment and expedited partner therapy (EPT) on genital tract cytokines among a cohort of young South African women. METHODS: HIV-negative women underwent POC testing for Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG) and Trichomonas vaginalis (TV) by Xpert CT/NG and OSOM TV, and for bacterial vaginosis (BV) by microscopy. Women with STIs and/or BV received immediate treatment, EPT for STIs and retested after 6 and 12 weeks. Concentrations of 48 cytokines were measured in cervicovaginal fluid at each visit using multiplex ELISA technology. The impact of STI treatment on cytokine concentrations was assessed by multivariable linear mixed models and principal component analysis. RESULTS: The study enrolled 251 women with median age of 23 years (IQR 21-27). The prevalence of CT, NG and TV were 14.3%, 4.4% and 4.0%, and 34.3% had BV. Women with STIs or BV at baseline (n=94) had significantly higher concentrations of pro-inflammatory cytokines (interleukin (IL)-1alpha, IL-1beta, IL-6, tumour necrosis factor (TNF)-alpha, TNF-beta, IL-18 and macrophage inflammatory factor (MIF)) and chemokines (IL-8, IL-16, macrophage inflammatory protein (MIP)-1alpha, IFN-alpha2, monokine induced by gamma interferon (MIG), monocyte chemoattractant protein (MCP)-3, regulated on activation normal T cell expressed and secreted and eotaxin) compared with women without (n=157). STI treatment was strongly associated with reduced concentrations of pro-inflammatory cytokines IL-6 (p=0.004), IL-1beta (p=0.013), TNF-alpha (p=0.018) and chemokines MIG (p=0.008) and growth-related oncogene (GRO)-alpha (p=0.025). A lower Nugent score was associated with a reduction in pro-inflammatory cytokines IL-1alpha (p=0.003), TNF-related apoptosis-inducing ligand (p=0.004), MIF (p=0.010) and IL-18 (p<0.001), but an increase in chemokines MIG (p=0.020), GRO-alpha (p<0.001), IP-10 (p<0.001), MIP-1beta (p=0.008) and MCP-1 (p=0.005). Principal component analysis showed differences in STI and BV-related inflammatory profiles, but that resolution restored a profile consistent with vaginal health. CONCLUSIONS: A comprehensive STI intervention effectively reduced genital inflammation among young women, thereby improving vaginal health and potentially reducing HIV risk.