Stable isotopes of carbon and oxygen in tree-ring cellulose are useful for elucidating tree physiological responses to environmental conditions. We examined d13C and d18O of tree-ring cellulose from Quercus rubra (L.) in the Midwestern US. We examined apparently healthy and declining trees, across multiple decades (1964 to 1994) encompassing relatively wet and drought periods. We tested the hypothesis that both isotope ratios decrease with increasing moisture availability, as predicted by theory. Tree-ring cellulose d13C values ranged from –25.7 to –22.4‰ and d18O values ranged from 26.9 to 31.0‰. Both d13C and d18O experienced this range of values during drought periods; during wetter years, the range of values were smaller, spanning ~1.2‰ and ~1.4‰ for d13C and d18O, respectively. Tree-ring cellulose d13C declined with tree age, regardless of drought status, contrary to expectations, and d18O exhibited no relationship with drought. The relationship between d13C and d18O was significant and positive, with r2 values ranging from 0.53 to 0.96 for categories describing tree health and drought severity. During a severe drought in 1981-1983, tree-ring cellulose became relatively 13C-deplete, while d18O declined. The apparent maintenance of physiological functioning as exhibited via d13C in conjunction with the decline in d18O during this drought suggests that all trees, regardless of apparent health status, accessed water from relatively deep within the soil profile compared to other time periods. As a result, neither d13C nor d18O exhibited a relationship with drought severity, contrary to theory. Variation in d18O was at least as significant as that in d13C, suggesting that source water d18O governed tree-ring cellulose d18O, not evaporative enrichment, in contrast with a recently published study. These data indicate the extent to which responses to environmental cues of d13C and d18O from non-phreatophytic trees may be mitigated when they can access deeper soil water.