A NanoSIMS 50L was used to study the relationship between the 235U/238U atomic and 235U16O/238U16O diatomic 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). The goal was to understand whether use of the 235U16O/238U16O resulted in improved accuracy and precision in comparison to the 235U/238U, since there is typically a greater abundance of 235U16O+ and 238U16O+ diatomic secondary ions in comparison to 235U+ and 238U+ atomic ions when uranium bearing materials are sputtered with an oxygen primary ion beam. For the UO2 and silicate reference materials, use of the 235U16O/238U16O resulted in improved precision and accuracy in comparison to the 235U/238U. 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 versus the 235U/238U from the other uranium compounds clearly indicates that the 235U16O/238U16O results in worse precision and accuracy. This behavior is tied to the observation that the atomic (235U+ and 238U+) to diatomic (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, as opposed to matrix effects, in the UO2F2, UO3, UO2(NO3)2·6(H2O), and UF4 may be a major contributing factor to the inconsistent relationship between the atomic and diatomic secondary ion yields. In total, the results suggest that, for certain bulk-compositions, use of the 235U16O/238U16O is a viable approach to improving the precision and accuracy in situations where there is expected to be a relatively low 235U+ count-rate.