Exacerbation reactions (ER) are acute reactions occurring locally in histoid or other highly active lepromatous lesions with an exceptionally heavy bacterial load. Clinically, they are almost silent although they may cause ulceration and the release of viable bacilli. Histologically, the influx of polymorph neutrophils and coincident macrophage degeneration mimic erythema nodosum leprosum (ENL). Later, the signs of increased permeability or necrosis of small blood vessels and mast cell degranulation are differential features. The predominant immunoglobulin is IgE, and the main complement component is C1q, C3 being mostly undetectable. The reactions appear to be mediated in part by reagins (although eosinophils are not seen). Immune complexes probably form at antigen excess. Of equal importance may be the release from highly activated macrophages and neutrophils of hydrolases and proteases, which are capable of degrading connective tissue and other cell surfaces. This report is based on a histopathological and an immunocytological study of 13 exacerbation reactions in comparison with nonreacting hyperactive lesions and with ENL. The results support the view that the essential feature of histoid lesions is their hyperactivity.