Objective To compare the effectiveness and cost-effectiveness of the recombinant Mycobacterium tuberculosis fusion protein skin test (EC) and the tuberculin skin test (TST) for detecting latent tuberculosis infection (LTBI), and to explore a more suitable screening method for LTBI in school students. Methods 283 high school freshmen enrolled in September 2021 in Chongqing City were divided into EC group (n=138) and TST group (n=145) by cluster random sampling. Each student was intracutaneously injected with 0.1 mL of either EC or TST into the left forearm, and skin reactions were observed 72 hours after injection. Before skin test, venous blood of all 283 students was collected for in vitro interferon-γ release assay (IGRA). Taking the IGRA test result as the standard, the sensitivity, specificity, misdiagnosis rate, and consistency between EC/TST and IGRA were calculated respectively. Cost-effectiveness of the three methods were compared. Results The sensitivity, specificity, misdiagnosis rate, and consistency rate of EC were 54.55%, 93.70%, 45.45%, and 90.58% respectively, while those of TST were 61.11%, 81.10%, 38.89%, and 78.62% respectively. The detection cost for detecting one tuberculosis infection case using TST, EC, and IGRA were 124.29 Yuan, 492.86 Yuan and 4 879.31 Yuan, respectively. Conclusion The consistency between EC and IGRA is good, and the specificity, consistency and cost-effectiveness of EC are higher than TST. EC is also easy to perform, making it a potential new screening method for LTBI among school students.