Oral mucositis is a complication common to many cancer therapies and produces considerable pain and morbidity. The present study reports a double-blind, prospective, randomized clinical trial testing the efficacy of a calcium phosphate mouth rinse (Caphosol) with fluoride treatments vs a standard regimen of fluoride rinsing and placebo tray treatments in 95 patients undergoing hematopoietic stem cell transplantation (HSCT). The days and severity of mucositis were prospectively evaluated. There were statistically significant decreases in days of mucositis (3.72 vs 7.22 P=0.001), duration of pain (2.86 vs 7.67, P=0.0001), dose of morphine (34.54 mg vs 122.78 mg), days of morphine (1.26 vs 4.02, P=0.0001) and days to the onset of engraftment ANC (absolute neurotrophil count)>200 mm(3) (11.12 vs 12.56) in the Caphosol and fluoride treatment group vs fluoride-rinse group, respectively. Caphosol, a neutral, supersaturated, Ca(2+)/PO(4)(3-) mouth rinse, used in combination with topical fluoride treatments, is superior to fluoride rinse alone in reducing the frequency, intensity and duration of oral mucositis in patients undergoing HSCT.