Women in Africa, especially young women, have very high HIV incidence rates that cannot be fully explained by behavioural risks. In the setting of syndromic management for sexually transmitted infections (STIs) and bacterial vaginosis (BV), the influence of these, particularly asymptomatic infections, on CD4+ T cell activation and inflammation in the genital tracts of adolescents from South Africa urgently needs to be addressed. The influence of genital inflammation on HIV acquisition in this group will be discussed. Our study found that HIV seroconversion was associated with raised genital inflammatory cytokines (including chemokines MIP-1α, MIP-1β and IP-10). The risk of HIV acquisition was significantly higher in women with evidence of genital inflammation, defined by at least 5 of 9 inflammatory cytokines being raised [OR 3.2; 95% confidence interval 1.3–7.9]. Genital cytokine concentrations were persistently raised (for about one year before infection), with no readily identifiable cause despite extensive investigation of several potential factors, including STIs and systemic cytokines. Adolescents (median 18 years) had significantly higher frequencies of activated CD4+ T-cells (CD38+, HLADR+, CD38+HLADR+) from cervical cytobrushes than adults, although CCR5 expression was higher in adults. STIs and BV prevalence was very high in certain areas of South Africa, with 71% of adolescents having >1 STI and/or BV, and 42% being C. trachomatis positive. Adolescents with an STI had higher frequencies of activated and proliferating T-cells compared to those with no STI/BV. Higher cervical T-cell activation marker expression was directly associated with increased genital cytokine profiles. Our data suggests that elevated genital concentrations of HIV target cell-recruiting chemokines and a genital inflammatory profile contributes to the high risk of HIV acquisition in these African women. In adolescents, heightened levels of genital immune activation and inflammation, partly due to the presence of asymptomatic STIs/BV, could increase their risk for HIV infection.