A novel complexation of sulfisoxazole with hydroxypropyl-β-cyclodextrin (HP-β-CD) was studied. Two systems were used: binary complexes prepared with HP-β-CD and multicomponent system (HP-β-CD and the basic compound triethanolamine (TEA)). Inclusion complex formation in aqueous solutions and in solid state were investigated by the solubility method, thermal analysis (differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA)), Fourier-transform infrared spectroscopy (FT-IR) and dissolution studies. The solid complexes of sulfisoxazole were prepared by freeze-drying the homogeneous concentrated aqueous solutions in molar ratios of sulfisoxazole:HP-β-CD 1:1 and 1:2, and sulfisoxazole:TEA:HP-β-CD 1:1:2. FT-IR and thermal analysis showed differences among sulfisoxazole:HP-β-CD and sulfisoxazole:TEA:HP-β-CD and their corresponding physical mixtures and individual components. The HP-β-CD solubilization of sulfisoxazole could be improved by ionization of the drug molecule through pH adjustments. However, larger improvements of the HP-β-CD solubilization are obtained when multicomponent systems are used, allowing to reduce the amount of CD necessary to prepare the target formulation.