HIV transmission rates are low on a per-coital level, but increased by various transmission co-factors. One implication of this is that the mucosal environment of female reproductive tract – in the case of male-to-female transmission – is generally capable of repelling the virus. Several lines of evidence have linked HIV transmission co-factors with altered mucosal immune parameters. Mucosal inflammation, defined by elevated cytokine concentrations in cervicovaginal secretions, was associated with increased rates of HIV acquisition in the CAPRISA 004 study. While the causes of these remain unclear, we have also shown that mucosal cytokines are associated with an altered mucosal proteome including impaired barrier function, and increased frequencies of HIV target cells in the mucosa. A further proteomic analysis of HIV cases and controls demonstrated that HIV outcome could be predicted with 97% accuracy on the basis of 10 key proteins. Proteins overrepresented in cases included those associated with inflammation, while barrier-associated proteins were overrepresented in controls. Application of this model to younger women, who in the sub-Saharan African epidemic represent the group with the highest incidence rates, will be important to understanding HIV risk. In particular, the role of sex work-related exposures including rates of condom use, partner change, vaginal practices, microbiome, and other infections in driving immune changes remains poorly described. A better understanding of HIV transmission at a mucosal level may reveal novel HIV prevention options.