Fatigue behavior of compact bone at physiological strain ranges was examined in vitro. Standardized specimens of bovine compact bone were cyclically loaded in uniaxial tension of 0-1200 or 0-1500 microstrain for up to 13-37 million cycles to study the long-term fatigue properties. All specimens exhibited fatigue during the first several million cycles of loading, evidenced by a gradual decrease of specimen modulus during this initial loading period; mean modulus loss for all specimens was approximately 6%. After this initial stiffness loss, specimen modulus stabilized and did not change again for the duration of the loading. Osteonal bone specimens lost significantly more stiffness than primary bone specimens during the early loading history, but neither microstructural type progressed to fatigue failure. These data suggest that some fatigue of compact bone is a realistic expectation of the normal loading environment, but this fatigue does not progress to fatigue failure within a physiologically reasonable number of cycles when tested in vitro at strain magnitudes like those measured in living animals. Implications for fatigue/stress fractures in vivo are discussed.