Th1 type cytokine responses are critical in the control of Mycobacterium tuberculosis infection. Recent findings indicate that 5-lipoxygenase–dependent (5-LO–dependent) lipoxins regulate host IL-12 production in vivo. Here, we establish lipoxins as key chemical mediators in resistance to M. tuberculosis infection. High levels of lipoxin A₄ (LXA₄) were detected in sera from infected WT but not infected 5-LO–deficient mice. Moreover, lungs from M. tuberculosis–infected 5-lo^–/– animals showed increased IL-12, IFN-γ, and NO synthase 2 (NOS2) mRNA levels compared with the same tissues in WT mice. Similarly, splenocyte recall responses were enhanced in mycobacteria-infected 5-lo^–/– versus WT mice. Importantly, bacterial burdens in 5-lo^–/– lungs were significantly lower than those from WT mice, and this enhancement in the resistance of the 5-lo^–/– animals to M. tuberculosis was completely prevented by administration of a stable LXA₄ analog. Together our results demonstrate that lipoxins negatively regulate protective Th1 responses against mycobacterial infection in vivo and suggest that the inhibition of lipoxin biosynthesis could serve as a strategy for enhancing host resistance to M. tuberculosis.