Background: It has been demonstrated that TLR2, TLR4 and TLR9 which were initially known for recognizing bacterial product are involved in detection of viral components. It was planned to undertake a prospective longitudinal study among ethnically homogenous ART and ATT naïve HIV-positive patients representing the north Indian population. The aim of the study was to investigate the influence of TLR2, TLR4 and TLR9 polymorphism in HIV disease progression. Methods: Present study was designed to investigate genetic polymorphism in TLRs (TLR2, TLR4 and TLR9) among HIV-infected patients with and without TB co-infection. The study population consisted of two groups (i) HIV-positive patients without TB infection and disease (n=223, HIV+ patients); (ii) HIV-positive patients with latent tuberculosis infection (n=150, HIV+LTBI patients). These subjects were of either gender between 18-60 year of age and treatment naïve for both TB and HIV. HIV+ and HIV+ LTBI patients were longitudinally followed-up for the period of two years to study HIV disease progression. Results: On comparing TLR2 and TLR4 allelic and genotypic frequencies between 306 HIV+ patients (no TB/AIDS) and 47 HIV+ patients progressed to active TB/AIDS, no significant difference was observed between two groups. The frequency of ‘A’ allele in TLR9 was found to be significantly increased in 47 HIV+ patients who progressed to active TB/AIDS (61.7%) as compared to 42.16% in 306 HIV+ patients (no TB/AIDS), (p<0.001). Also, a significant increased frequency of ‘AA’ genotype in TLR9 was observed in 47 HIV+ patients progressed to active TB/AIDS (55.32%) as compared to 20.26% in HIV+ patients (no TB/AIDS). Conclusions: Findings of the present study revealed that genetic variability in TLR9 may influence the HIV disease progression. The AA genotype in TLR9 may be associated with progression to TB/AIDS during 2-year time period in HIV+ patients.