Aimed at exploring the influence of acetic acid on crystallization thermodynamics of cefotaxime sodium (CTX), the solubility of CTX in ethanol + water mixtures under acetic acid conditions at various temperatures are measured by a gravimetrical method. Different from the solubility curve when acetic acid is absent, the solubility curves of CTX under acetic acid conditions have a maximum value. The maximum solubility drifts as temperature varies, which is related to the dielectric constants of solvent mixtures. A combination of the Jouyban-Acree model and Apelblat equation is used to correlate the solubility data, and the correlation precision is improved when compared with that of the Jouyban-Acree model. By using the Wilson model, the activity coefficients of CTX and the mixing Gibbs free energies, enthalpies, and entropies of CTX solution are also predicted. The data presented in this study explain why the crystallization of CTX in ethanol + water mixtures is difficult and are helpful for guiding the industrial reaction and crystallization process of CTX.