A significant reduction in and a change in the character of fuel-cladding chemical interaction (FCCI) due to a reduction in the oxygen-to-metal ratio (O/M) was established for uranium-plutonium mixed-oxide fuels clad with 20% cold-worked Type 316 stainless steel irradiated in the Experimental Breeder Reactor II. Fuel pins from the Hanford Engineering Development Laboratory P-23C subassembly at initial fuel O/Ms of 1.94, 1.95, and 1.97 were examined at peak burnups of 1.1, 2.5, and 3.6 at.%. The depth of FCCI increased with increasing burnup and temperature, but the relative effects of fuel O/M did not change. An approximate three-fold reduction in FCCI resulted from a reduction in fuel O/M from 1.97 to 1.95 at ∼3.6 at.%) burnup. The peak FCCI in the lower O/M fuel was ∼5 μm and appeared as a preferential loss of cladding at grain boundaries and slip planes on the cladding inner surface. In contrast, the typical FCCI in the higher O/M (1.97) fuel pin was matrix in character, and penetrated ∼14 μm into the cladding. Thus, FCCI in mixed-oxide fuel can be reduced to negligible levels by lowering the O/M during manufacture of the fuel.