The present study analyzes some clinical and immunological aspects of the giant reaction (GR) in lepromatous leprosy. Sixteen out of a total of 147 (10.9%) lepromatous patients developed the clinical features of GR upon the intradermal administration of PPD; most (14 of 16) GRs occurred in bacteriologically positive cases. GR precipitated an episode of erythema nodosum leprosum (ENL) in three patients. In addition, patients with GR showed enhanced in vitro response to PPD, by the lymphoproliferation test and interferon-gamma assay, as compared to either PPD-negative individuals or PPD-positive patients without GR. Therefore, cell-mediated-immune response to mycobacterial antigens is present in lepromatous patients with GR. It is suggested that the exacerbated in vivo response to PPD in lepromatous leprosy is the result of an increased immunoreactivity to the antigen, which well may be associated with the local and/or systemic release of cytokines [tumor necrosis factor-alpha (TNF alpha) and interferon-gamma (IFN gamma)] by the inflammatory cells. These episodes may, in fact, play an important role in determining the development of disabilities and reactional states, thereby interfering with the prognosis of leprosy disease.