The stability and compatibility of fluorouracil admixtures with mannitol during simulated Y-site administration was studied. Fluorouracil injection 50 mg/mL was diluted with 5% dextrose injection, 0.9% sodium chloride injection, and 5% dextrose and 0.45% sodium chloride injection to final concentrations of 1 and 2 mg/mL. Combinations of fluorouracil admixtures with 20% mannitol injection were made using equal volumes in glass test tubes; immediately after mixing and at one, two, and four hours, the samples were examined for visual incompatibilities. Duplicate combinations of fluorouracil admixtures with 20% mannitol injection were made using equal volumes in plastic syringes; immediately after mixing with internal standard in glass test tubes and at 2, 4, 8, and 24 hours, samples were removed for chemical analysis. A high-performance liquid chromatographic assay was used to determine fluorouracil concentrations. No evidence of precipitation, color change, or haze was observed. During the 24-hour study, fluorouracil concentrations remained within 6% of initial concentrations for all combinations with mannitol. Fluorouracil 1 and 2 mg/mL in 5% dextrose injection, 0.9% sodium chloride injection, and 5% dextrose and 0.45% sodium chloride injection was chemically stable and visually compatible when combined with 20% mannitol injection during simulated Y-site administration.