Fibroblast growth factor 1 is a powerful mitogen playing an important role in morphogenesis, angiogenesis and wound healing and is therefore of potential medical interest. Using homologous sequence and structure comparisons, we designed and constructed 16 mutants of FGF-1 with increased thermodynamic stability, as determined by chemical and heat denaturation. For multiple mutants, additive effects on stability were observed, providing mutants up to 7.8 degrees C more stable than the wild-type. None of the introduced mutations affected any FGF-1 biological activities, such as stimulation of DNA synthesis, MAP kinase activation and binding to the FGF receptor on the cell surface. Our study provides a good starting point to improve the stability of FGF-1 in the context of its wide potential therapeutic applications. We showed that a homology approach is an effective method to change the thermodynamic properties of the protein without altering its function.