Background Identification of the immune response against tuberculosis is vital to develop new diagnostic and therapeutic modalities. The objective of this study was to determine IL (interleukin)-18 and IL-27 responses of peripheral blood mononuclear cells to early secreted antigen (ESAT-6) and culture filtrate protein-10 (CFP-10) stimulation in children with a (+) or (-) tuberculin skin test (TST) with in-house tuberculosis contact. Methods We enrolled 40 children aged 1 to 5 years who had an in-house contact with a tuberculous adult. Blood samples were obtained from all children for QuantiFERON tuberculosis (TB) gold in tube (QFT-GIT), and peripheral blood mononuclear blood cell culture tests. The subjects were grouped as TST (-) QFT-GIT (-), TST (+) QFT-GIT (-), and TST (+) QFT-GIT (+). Supernatant of peripheral blood mononuclear cell culture was separated with and without stimulation of ESAT-6 and CFP-10, and IL-18 and IL-27 levels were measured with enzyme linked immunoassay (ELISA) test. Results The study group included 22 boys and 18 girls with mean age 4.25 +/- 0.9 years. IL-18 and IL-27 levels were statistically significant in ESAT-6/CFP-10-stimulated supernatants of peripheral blood mononuclear cell (PBMC) samples among the three groups (p = 0.000,p = 0.007, respectively). IL-18 levels between the TST (-) QFT-GIT (-) and TST (+) QFT-GIT (+) groups were significantly different (p = 0.026). Both IL-18 and IL-27 levels were significantly different between ESAT-6/CFP-10 stimulated PBMC supernatants of TST (-) QFT-GIT (-) and TST (+) QFT-GIT (-) groups (p = 0.000,p = 0.003, respectively). Conclusion Low IL-18 and IL-27 responses of peripheral blood mononuclear cells in children with Bacillus Calmette-Guerin (BCG) vaccine may play a role inMycobacterium tuberculosisinfection after in-house contact.