Francisella tularensis, a bacterium which causes tularemia in humans, is classified as a CDC category A bioterrorism agent. In this study, we demonstrate that celecoxib, an anti-inflammatory cyclooxygenase-2 inhibitor in clinical use, exhibits activity against a type A strain of F. tularensis (Schu S4), the live vaccine strain of F. tularensis (a type B strain), and F. novicida ("F. tularensis subsp. novicida") directly in growth medium. This bacterial killing, however, was not noted with rofecoxib, despite its higher potency than that of celecoxib in inhibiting cyclooxygenase-2. The unique ability of celecoxib to inhibit the proliferation of F. tularensis could be pharmacologically exploited to develop novel anti-Francisella therapeutic agents, of which the proof of principle is demonstrated by compound 20, a celecoxib derivative identified through the screening of a celecoxib-based focused compound library. Compound 20 inhibited the intracellular proliferation of Francisella in macrophages without causing appreciable toxicity to these host cells. Together, these data support the translational potential of compound 20 for the further development of novel, potent anti-Francisella agents.