Mycobacterium tuberculosis (MTB) and Mycobacterium avium (MA) belong to the intracellular parasitic bacteria. To better understand how MTB survives in macrophages and the different pathogenic mechanisms of MTB and MA, the tandem mass tag (TMT) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) were used for analysis of the differentially expressed proteins in MTB-infected macrophages and MA-infected macrophages. A total of 682 proteins were found to be differentially expressed in MTB-infected cells in comparison with MA-infected cells. Gene Ontology annotation revealed the involvement of 682 differentially expressed proteins in cellular components, biological processes and molecular functions including binding, catalytic activity, metabolic processes, cellular processes, cell part, cell proliferation and apoptosis, etc. Among these, 10 proteins (O60812, P06576, O43660-2, E9PL10, O00442, M0R050, Q9H8H0, Q9BSJ8, P41240 and Q8TD57-3) were down-regulated in MTB-infected cells. We found that M0R050, O00442, Q9H8H0, O60812 and O43660 are interactive proteins which participate in a multitude of cellular RNA processing, suggesting that these five down-regulated proteins might repress the synthesis of some resistant proteins in MTB-infected cells to promote MTB survival in macrophages.