Topical and systemic administration or contact with fluorides has produced various forms of cutaneous reactivity. These studies, conducted with 150-400 g. Sprague-Dawley rats, investigated the effect of topical application of NaF to a shaved, epidemal abraded region (5 em.) of dorsal skin. After 24 hrs. NaF (1%) produced inflammation of the epithelial keratin and the formation of intraepidermal vesicles abundant in fluid, polymorphonuclear leukocytes, lymphocytes, and erythrocytes. Edematous subendothelial changes were noted with cellular hypochromicity. Electron microscopy revealed extensive mitochondrial vacuolization. The cutaneous vesicles persisted for approximately 7 days after NaF application. In rats treated with NaF (N=23) skin histamine levels were significantly (p<.01) elevated (H=90.48 ug/g ± S.D.=32.4) above those for NaCl-treated (N=29; 33.52 ± 9. 75 ug/g), H20-treated N=23; 32. 35 ± 9. 25 ug/g), or shaved only rats (N=20; 26.55 ± 3. 86 ug/g). In non-abraded skin NaF did not produce either chemical or histological changes. No further increase in vesicle fomation or histamine elevation was produced by prolonging the duration of topical application. The accumulation of histamine as a result of Na-P-induced inhibition of diamine oxidase, or enzymes of the skin glycolytic pathway providing for increased Ca++ availability, may explain the present data.