Chlamydia trachomatis is the most prevalent sexually transmitted bacterium in the world with almost 100 million new cases each year, some of which will develop tubal pathology. Clear differences in its clinical course of infections have been observed, and recently it has been shown that 40% is based on host genetic factors. We used an integrated approach based on infection of Toll-like receptor 4 (TLR4) knockout mice and immunogenetic analysis of female sexually transmitted disease (STD) patients (susceptibility) and women with C. trachomatis-associated tubal factor subfertility (severity). The results in TLR4 knockout mice suggest that the protection against reinfection is more solid in normal as compared to the TLR4-deficient mice. In humans the functional TLR4 single nucleotide polymorphism studied was not involved in the susceptibility to infection. However, C. trachomatis immunoglobulin (Ig) G-positive subfertile women with tubal pathology were more than twice as likely to be carriers of the mutant TLR4 +896 G allele as compared to those without tubal pathology; however this observation did not reach statistical significance. In conclusion, both the murine model and the human immunogenetics studies show a slight effect upon TLR4 deficiency in the severity of infection but not in the susceptibility to infection. Copyright 2009 Prous Science, S.A.U. or its licensors. All rights reserved.