Gamma interferon (IFN-gamma) is a crucial cytokine for protection against Mycobacterium tuberculosis, but the mechanism of IFN-gamma transcription is still unclear. The cyclic AMP (cAMP) responsive element binding (CREB) proteins belong to the bZip (basic leucine zipper) family of transcription factors and are essential for T-cell function and cytokine production. This study focused on the capacity of CREB proteins to regulate IFN-gamma transcription in CD3(+) T cells obtained from tuberculosis (TB) patients and persons with latent tuberculosis infection (LTBI) in China. The electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), and Western blotting were used to demonstrate the regulatory role of CREB. EMSA (in vitro) and ChIP (in vivo) experiments suggested CREB could bind to the IFN-gamma proximal promoter in persons with LTBI, whereas no binding was detected in TB patients. Western blotting confirmed the expression of CREB proteins, especially serine-133-phosphorylated CREB, was markedly reduced in TB patients compared with persons with LTBI. These results suggested that CREB could promote the transcription and production of IFN-gamma through binding with the IFN-gamma proximal promoter, but the regulatory role of CREB was decreased in tuberculosis patients owing to diminished expression of CREB proteins, which in turn reduced the IFN-gamma production.