The origins of sickle-cell disease (SCD) are well understood, as are its evolutionary pressures on humans and pathological presentation. However, because it has not been possible to identify SCD in archaeological contexts, its biocultural effects on past populations are unknown. Previous research investigating oxygen isotope fractionation during respiration among anemics suggests that oxygen isotopes in bone apatite may provide a biological marker for SCD in skeletal remains. This pilot study reports δ18O ratios in bone apatite of transgenic laboratory mice expressing human SCD globins and compares them to healthy control mice. The δ18O ratios of sick mice are significantly lower than those of healthy mice (−5.6‰ vs. −4.5‰; P = 0.002), and the sickest mice exhibit the lowest ratios of all (mean δ18O = −5.8‰). These preliminary results suggest that this method may be usefully applied to skeletal materials of past human populations whose diets and water sources do not differ substantially. Am J Phys Anthropol, 2011. © 2011 Wiley-Liss, Inc.