Failure of bone adaptation to protect the skeleton from fatigue fracture is common, and site-specific accumulation and coalescence of microcracking in regions of high strain during cyclic loading is considered a key factor that decreases the resistance of whole bones to fracture. We investigated the effect of cyclic fatigue loading on the monotonic structural properties of the rat ulna during accumulation and coalescence of microcracks. Cyclic end-loading of the ulna was performed at 4 Hz ex vivo at an initial peak strain of -6000 muepsilon to 20% loss of stiffness (n = 7) or 40% loss of stiffness (n = 7) bilaterally. A 0% loss of stiffness monotonically loaded control group (n = 7) was also included. Volumetric bone mineral density (vBMD), ultimate strength (F(u)), stiffness (S), and energy-to-failure (U) were determined in one ulna and in the contralateral ulna vBMD, cortical bone area (B.Ar), maximum and minimum second moments of inertia (I(MAX) and I(MIN)), microcrack density (Cr.Dn), microcrack mean length (Cr.Le), and microcrack surface density (Cr.S.Dn) were determined. In two additional groups of rats, cyclic end-loading of the ulna was also performed ex vivo unilaterally to 20% loss of stiffness (n = 10) and 40% loss of stiffness (n = 10) and then vBMD, F(u), S, U, B.Ar, I(MAX), and I(MIN) were determined bilaterally. Fatigue loading had incremental degradative effects on ulna structural properties. This decreased resistance to fracture was associated with accumulation and coalescence of branching arrays of microcracks within the cortex of the ulna. Microcracking was most prominent in the middiaphysis and corresponded to the region of the bone that fractured during monotonic structural testing. Fatigue loading influenced the relationship between bone cross-sectional geometry and vBMD and ulna structural properties. At 40% loss of stiffness, F(u), S, and U were all significantly correlated with cross-sectional bone geometry and vBMD, whereas this was not the case at 20% loss of stiffness and with the 0% loss of stiffness monotonic control ulnae. We also found a biologically significant individual animal effect. Larger ulnae required a higher number of load cycles for fatigue to develop, retained higher strength, and accumulated a greater amount of microcracking at the end of the cyclic fatigue testing. Small increases in bone size and density can substantially improve the resistance of whole bones to fracture as microcracking accumulates and coalesces during cyclic fatigue loading.