Microparticles composed of poly (DL-lactide-co-glycolide) (DL-PLG) were used as delivery vehicles for evaluating the immunoreactive and immunoprotective properties of 71-kDa cell wall associated protein of Mycobacterium tuberculosis H37Ra. Mice immunized with 71-kDa microparticles entrapped in DL-PLG (PLG-MPs) exhibited significantly higher T-cell stimulation and cytokine release in comparison to 71-kDa emulsified in Freund's incomplete adjuvant (FIA) as well as a BCG vaccinated group throughout the post-immunization (p.im.) period. Further, the protective efficacy of 71-kDa was evaluated on the basis of survival rates and viable bacilli load in different organs at 30 days post challenge (p.c.), with the median lethal dose (LD50) of M. tuberculosis H37Rv at weeks 8 and 16 p.im. Both 71-kDa-PLG and 71-kDa-FIA immunized groups exhibited a comparable protection (90%) which was significantly higher (P < 0.5) than in the BCG group (70%) at week 8 p.im. and it was consistent with the decreased bacterial load in the target organs. However, on increasing the interval of challenge to 16 weeks p.im., the protective efficacy of 71-kDa-PLG was sustained (85%) while that of 71-kDa-FIA began to wane (70%). Further. the 71-kDa-PLG immunized group exhibited a significantly higher (P < 0.001) clearance of bacterial load from the lungs and livers in comparison to the 71-kDa-FIA immunized group. The results suggest the long-term protective potential of a PLG-microparticle based antigen delivery system for tuberculosis.