Childhood tuberculosis is difficult to diagnose. A rapid, simple and relatively inexpensive diagnostic test will be crucial to future control efforts. Therefore, efficacy and diagnostic potential of different secretory antigens of Mycobacterium tuberculosis (CFP-10, Ag85complex, Ag85 A, B, C) and their combinations along with ESAT-6 in the detection of antibody profiles of childhood tuberculosis cases were evaluated using ELISA technique and reactivity was compared with the gold standards (smear, culture and IS6110 targeted PCR). In the present study, 88 fresh, untreated childhood tuberculosis (TB) cases, 17 children undergoing anti-tubercular therapy, 17 children having disease other than TB and 25 healthy children were included. ROC curve analysis was used to calculate the sensitivity and specificity of each antigen for antibody detection. Ag85C was found to be showing highest sensitivity of 89.77% and specificity of 92% among all the antigens used (P < 0.0001). Positivity with antigen was 95% in smear and culture negative patients. Antibody reactivity was noted in 92.62% of patients who were positive for IS6110 by PCR. Cocktail of all the antigens showed 67.1% sensitivity and 80% of specificity. Sensitivity of 29.55%, 57.95%, 64.77% and specificity of 80%, 72%, 64% was observed using CFP-10, Ag85complex and Ag85B. Low reactivity of 31.82% in patients and least specificity of 24% was noted with Ag85A. Our finding demonstrates the potential of Ag85C in the detection of antibody in childhood TB cases and this antigen showed good concordance with PCR positivity.