Problems of logistics, compliance and drug resistance point to an urgent need for immunotherapeutic strategies capable of shortening the current six month antibiotic regimens used to treat tuberculosis. One potential immunotherapeutic agent is transfer factors. Transfer factors (TF) are low molecular weight dialysable products from immune cells which transmit the ability to express delayed-type hypersensitivity (DTH) and cell mediated immunity from sensitized donors to nonimmune recipients. In this study we determined the efficiency of TF as immunotherapy to treat experimental tuberculosis. When BALB/c mice are infected via the trachea with Mycobacterium tuberculosis H37Rv there is an initial phase of partial resistance dominated by Th-1 type cytokines plus tumour necrosis factor-alpha (TNFalpha) and the inducible isoform of nitric oxide synthase (iNOS), followed by a phase of progressive disease characterized by increasing expression of IL-4, diminished expression of TNFalpha and iNOS, and low DTH. Animals in this late progressive phase of the disease (day 60) were treated with different doses of TF (one injection per week) obtained from spleen cells when the peak of immune protection in this animal model is reached (day 21), or with different doses of TF from peripheral leucocytes of PPD + healthy subjects. We show here that the treatment with murine or human TF restored the expression of Th-1 cytokines, TNFalpha and iNOS provoking inhibition of bacterial proliferation and significant increase of DTH and survival. This beneficial effect was dose dependent. Interestingly, murine TF in combination with conventional chemotherapy had a synergistic effect producing significant faster elimination of lung bacteria loads than chemotherapy alone.