The blue-green microalgae spirulina, used in daily diets of natives in Africa and America, has been found to be a rich natural source of proteins, carotenoids and other micronutrients. Experimental studies in animal models have demonstrated an inhibitory effect of spirulina algae on oral carcinogenesis. Studies among preschool children in India have demonstrated spirulina fusiformis to be a effective source of dietary vitamin A. We evaluated the chemoproventative activity of spirulina (1 g/day for 12 months) in reversing oral leukoplakia in pan tobacco chewers in Kerala, India. Complete regression of lesions was observed in 20 of 44 (45%) evaluable subjects supplemented with spirulina, as opposed to 3 of 43 (7%) in the placebo arm. When stratified by type of leukoplakia, the response was more pronounced in homogeneous lesions: complete regression was seen in 16 of 28 (57%) subjects with homogeneous leukoplakia, 2 of 8 with erythroplakia, 2 of 4 with verrucous leukoplakia, and 0 of 4 with ulcerated and nodular lesions. Within one year of discontinuing supplements, 9 of 20 (45%) complete responders with spirulina developed recurrent lesions. Supplementation with spirulina did not increase serum concentrations of retinal or beta carotene, nor was it associated with toxicity. This is the first human study evaluating the chemopreventive potential of spirulina. More studies in different settings and different populations are needed for further evaluations.