Background. Candida albicans infection has been proposed to cause a chronic hypersensitivity syndrome characterized by fatigue, premenstrual tension, gastrointestinal symptoms, and depression. long-term antifungal therapy has been advocated as treatment for the syndrome, which is most often diagnosed in women with persistent or recurrent candida vaginitis. Methods. To determine the efficacy of nystatin therapy for presumed candidiasis hypersensitivity syndrome, we conducted a 32-week randomized, double-blind, crossover study using four different combinations of nystatin or placebo given orally or vaginally in 42 premenopausal women who met preset criteria for the syndrome and had a history of candida vaginitis. The outcomes studied were the changes from base line in scores for vaginal, systemic, and overall symptoms and in the results of standardized psychological tests. Results. The three active-treatment regimens (oral and vaginal nystatin, oral nystatin and vaginal placebo, and oral placebo and vaginal nystatin) and the all-placebo regimen significantly reduced both vaginal and systemic symptoms (P<0.001), but nystatin did not reduce the systemic symptoms significantly more than placebo. On average, the scores for systemic symptoms improved 25 percent with the three active-treatment regimens and 23 percent with the all-placebo regimen, a difference of only 2 percent (95 percent confidence interval, −3 to 7 percent). As expected, the three active-treatment regimens were more effective than placebo in relieving vaginal symptoms (P<0.001). All four regimens reduced psychological symptoms and global indexes of distress; there were no significant differences among the treatment regimens. Conclusions. In women with presumed candidiasis hypersensitivity syndrome, nystatin does not reduce systemic or psychological symptoms significantly more than placebo. Consequently, the empirical recommendation of long-term nystatin therapy for such women appears to be unwarranted. (N Engl J Med 1990; 323:1717–23.). © 1990, Massachusetts Medical Society. All rights reserved.