Adult-onset Still's disease (AOSD), an autoinflammatory syndrome of unknown etiology, typically manifests with spiking fevers, polyarthritis, and characteristic evanescent rash. We describe a young woman with AOSD complicated by calf fasciitis that serendipitously responded to clarithromycin administered for another indication. Remarkable improvement followed rechallenges with clarithromycin for subsequent AOSD flares. In addition to their antibacterial actions, macrolides demonstrate immunomodulatory effects, including suppression of proinflammatory cytokine production and neutrophil action. Previous clinical trials provide promising preliminary evidence of a therapeutic effect of macrolides in chronic inflammatory diseases. Although AOSD pathogenesis remains unclear, a role for dysregulation of innate immunity is supported by recent literature. Based on this possible innate immune mechanism, we suspect that macrolides may have induced a therapeutic response in this patient with AOSD. A clinical trial is warranted to establish or refute their therapeutic efficacy.