The stability of the trimethoprim/sulfamethoxazole (1:5, w/w) combination suitable for administration by injection was investigated to determine the nature of solid phases that can separate after dilution with infusion fluids. Phase-solubility analysis was performed on the binary system in water and in buffered aqueous media (pH 7 and 9), thus allowing a comprehensive picture of solid-solution compositions. Commercial samples of this combination were tested for solid phases separating after dilution with various infusion fluids. The interaction between trimethoprim and sulfamethoxazole, forming a 1:1 molecular compound with low solubility in water, is mainly responsible for the physicochemical properties of mixtures of these drugs in solution. Other solid phases (i.e., trimethoprim monohydrate and sulfamethoxazole emihydrate) can separate on long-term standing of solutions, depending on the value of the pH of the medium and the fluid used for dilution.