The stability and compatibility of dexamethasone sodium phosphate and hydromorphone hydrochloride or diphenhydramine hydrochloride at various concentrations at room temperature was studied. Solutions containing equal volumes in the following ranges of concentrations were prepared: dexamethasone sodium phosphate 0-10 mg/mL, diphenhydramine hydrochloride 0-50 mg/mL, and hydromorphone hydrochloride 0-40 mg/mL. Samples of each combination were analyzed immediately after mixing and at 7 and 24 hours using a stability-indicating high-performance liquid chromatographic assay. The pH of each solution was measured, and each combination was visually inspected. Precipitation occurred in solutions containing dexamethasone and hydromorphone hydrochloride or diphenhydramine hydrochloride when equal volumes of the most concentrated solutions were mixed. Some of the combinations at lower concentrations were visually compatible, and more than 90% of the initial concentrations of both drugs (i.e., dexamethasone-hydromorphone and dexamethasone-diphenhydramine) remained in these compatible solutions. Dexamethasone is visually compatible with diphenhydramine or hydromorphone but only within specific concentration ranges. In visually compatible solutions, both drug combinations are stable for up to 24 hours at room temperature.