The binding of irinotecan to serum proteins (hemoglobin, globulin and human serum albumin) was studied on the surface of epoxide modified superparamagnetic iron oxide nanoparticles (GPTS-SPIONs), which were synthesized by the coprecipitation of ferrous and ferric salts with NH4OH and then modified with [3-(2,3-epoxypropoxy)propyl] trimethoxy silane (GPTS) to obtain functional epoxide groups on the SPIONs’ surface. Results were compared to find an alternative as drug carries system. Data showed that binding amount of human serum albumin (HSA), globulin (Glb) and hemoglobin (Hb) found to be as 44, 21.2 and 32.6 μg per 20 mg of GPTS modified SPIONs, respectively. The thermal behavior of the serum protein–Ir interaction on GPTS-SPIONs was also studied by using thermo gravimetric analysis (TGA) technique and then the kinetic parameters for the thermal decomposition were determined using Horowitz–Metzger method.