The Reduced Enrichment for Research and Test Reactors (RERTR) program has been developing low-enrichment fuel systems encased in Al-6061 for use in research and test reactors. U-Mo alloys in contact with Al and Al alloys can undergo diffusional interactions that can result in the development of interdiffusion zones with complex fine-grained microstructures composed of multiple phases. A monolithic fuel currently being developed by the RERTR program has local regions where the U-Mo fuel plate is in contact with the Al-6061 cladding and, as a result, the program finds information about interdiffusion zone development at high temperatures of interest. In this study, the microstructural development of diffusion couples consisting of U-7wt.%Mo, U-10wt.%Mo, and U-12wt.%Mo vs. Al-6061 (or 6061 aluminum) cladding, annealed at 500, 550, 600°C for 1, 5, 20, 24, or 132 hours, was analyzed by backscatter electron microscopy and x-ray energy dispersive spectroscopy on a scanning electron microscope. Concentration profiles were determined by standardized wavelength dispersive spectroscopy and standardless x-ray energy dispersive spectroscopy. The results of this work shows that the presence of surface layers at the U-Mo/Al-6061 interface can dramatically impact the overall interdiffusion behavior in terms of rate of interaction and uniformity of the developed interdiffusion zones. It further reveals that relatively uniform interaction layers with higher Si concentrations can develop in U-Mo/Al-6061 couples annealed at shorter times and that longer times at temperature result in the development of more non-uniform interaction layers with more areas that are enriched in Al. At longer annealing times and relatively high temperatures, UMo/Al-6061 couples can exhibit more interaction compared to U-Mo/pure Al couples. The minor alloying constituents in Al-6061 cladding can result in the development of many complex phases in the interaction layer of U-Mo/Al-6061 cladding couples, and some phases in the interdiffusion zones of U-Mo/Al-6061 cladding couples are likely similar to those observed for U-Mo/pure Al couples.