A NanoSIMS 50 L was used to study the relationship between the 235U/238U atomic and 235U16O/238U16O molecular uranium isotope ratios determined from a variety of uranium compounds (UO2, UO2F2, UO3, UO2(NO3)2·6(H2O), and UF4) and silicates (NIST-610 glass and the Plesovice zircon reference materials, both containing µg/g uranium). Because there is typically a greater abundance of 235U16O+ and 238U16O+ molecular secondary ions than 235U+ and 238U+ atomic ions when uranium-bearing materials are sputtered with an oxygen primary ion beam, the goal was to understand whether use of 235U16O/238U16O has the potential for improved accuracy and precision when compared to the 235U/238U ratio. The UO2 and silicate reference materials showed the greatest potential for improved accuracy and precision through use of the 235U16O/238U16O ratio as compared to the 235U/238U ratio. For the UO2, which was investigated at a variety of primary beam currents, and the silicate reference materials, which were only investigated using a single primary beam current, this improvement was especially pronounced at low 235U+ count rates. In contrast, comparison of the 235U16O/238U16O ratio versus the 235U/238U ratio from the other uranium compounds clearly indicates that the 235U16O/238U16O ratio results in worse precision and accuracy. This behavior is based on the observation that the atomic (235U+ and 238U+) to molecular (235U16O+ and 238U16O+) secondary ion production rates remain internally consistent within the UO2 and silicate reference materials, whereas it is highly variable in the other uranium compounds. Efforts to understand the origin of this behavior suggest that irregular sample surface topography, and/or molecular interferences arising from the manner in which the UO2F2, UO3, UO2(NO3)2·6(H2O), and UF4 were prepared, may be a major contributing factor to the inconsistent relationship between the observed atomic and molecular secondary ion yields. Overall, the results suggest that for certain bulk compositions, use of the 235U16O/238U16O may be a viable approach to improving the precision and accuracy in situations where a relatively low 235U+ count rate is expected.