The current research focuses on laser melting and successive analysis of laboratory-scale uranium dioxide nuclear fuel samples in direct contact with Zircaloy-4 cladding. The goal was to characterize the melted and refrozen interfaces, in particular, observing local changes of the melting point and interdiffusion of fuel and cladding materials under inert gas (Ar), in the presence of hydrogen (Ar + 6% H2) or in air. Results obtained by laser heating UO2 pellets clad in a Zircaloy ring were interpreted in light of reference tests performed on pellets in which UO2 and zirconium were blended in a series of given compositions. The sample composition was analyzed by scanning electron microscopy to verify the occurrence of diffusion and segregation phenomena during the laser-heating cycles. Laser-melting experiments were performed on pellets of uranium dioxide clad in Zircaloy-4 rings to simulate the configuration of a light water reactor fuel rod. Under inert gas, the material interdiffusion resulted in consistent melting point depression (of up to 200 K below the melting point of pure UO2) at the interface between the fuel and the cladding. Experiments carried out in the presence of H2 displayed a more limited effect on the melting temperature, but they resulted in a remarkable embrittlement of the whole structure, with large fragmentation of the Zircaloy cladding. This was probably due to the formation of brittle and highly volatile Zr hydrides. The observed melting point decrease was even more pronounced (up to over 400 K) under air in uranium-rich samples, due to the change in the stoichiometry of UO2 in UO2+x.