As an immunomodulator, melatonin reportedly exhibits protective effects in severe sepsis/shock induced by bacterial lipopolysaccharides in animal models. The present study was conducted to evaluate the possible protective effects of melatonin against experimental Candida sepsis in rats. A total of 40 adult male Wistar rats were randomly assigned to 4 groups: control, melatonin-treated control, septic, and melatonin-treated septic. Melatonin (200 microg/kg/d, intraperitoneally) injections were begun a week prior to sepsis induction and were continued daily for 3 wk until the end of the study. Cyclophosphamide was administered to animals in all groups as an immunosuppressive agent as a single dose 4 d prior to yeast inoculation. To cause sepsis, the Candida albicans (ATCC 10259) strain was administered intravenously. Amphotericin B was given as an antimycotic therapeutic agent as a single dose to septic rats. Plasma levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), vascular cell adhesion molecule-1, and E-selectin were measured on the first and 15th days of sepsis. IL-6, TNF-alpha, vascular cell adhesion molecule-1, and E-selectin levels of septic rats were higher than those of controls. Melatonin reduced IL-6 levels and shortened time to improvement in animals with Candida sepsis. Levels of TNF-alpha and adhesion molecules in melatonin-treated septic rats were decreased compared with those in septic rats, but this difference was not statistically significant. In light of the current results, investigators conclude that melatonin may have therapeutic benefits in Candida sepsis and in classic antimycotic treatment because of its immune regulatory effects.