Microparticles (MP) are small membranous particles (100-1000nm) released from all cells under normal steady-state conditions. Previous work from our group demonstrated that M. tuberculosis (M.tb) infection of macrophages increases MP release. These MPs were proinflammatory in both in vivo and in vitro models. To determine how M.tb infection modulates the protein composition of the MPs and if this contributes to their proinflammatory nature we profiled and compared the proteomes of MPs derived from M.tb infected (TBinf-MP) and uninfected human macrophages. Mass spectrometry analysis identified 68 proteins with statistically significant differences in abundance. Of the 42 proteins increased in abundance in TBinf-MPs were proteins associated with immune function (7), lysosomal/ endosomal maturation (4), vesicular formation (12) and antigen processing (9). This included a number of type I interferon inducible proteins; ISG15, IFIT1, IFIT2, and IFIT3. Furthermore, transfer of these MPs to uninfected THP-1 cells increased gene expression of isg15, ifit1, ifit2, and ifit3 and induced the release of proinflammatory cytokines including IP-10. Humans with inherited ISG15 deficiency are highly susceptible to mycobacterial but not viral diseases. These data demonstrate that M.tb infection modulates the protein profile of MPs in particular those induced by type I interferon signalling pathways including ISG15 and IFITs. These proteins may regulate the proinflammatory potential of the MPs and provide a candidate biomarker of M.tb infection for further investigation.