Tests were performed on compact tension aluminum-alloy specimens with a keyhole notch that allowed natural crack formation and growth to failure under a programmed block representation of the TWIST load spectrum. The spectrum was rearranged as LoHi and HiLo sequences in order to introduce load history effects associated with stress-strain hysteresis at the crack tip. Quantitative fractography was then performed on the fatigue fractures to determine crack extension under individual load levels of the spectrum. The experimental measurements of crack growth rate in individual steps of the load spectrum were then compared with computed estimates starting from crack size a fraction of a millimeter. The computations were based on a dual mechanism model that accounts for both crack closure and the effect of near-tip residual stress, σ*, on intrinsic threshold stress intensity, ΔK_th,i. The analytical estimates assumed a constant crack closure level between 25% and 30% of maximum applied load. The LoHi/HiLo sequence effect was entirely accounted for by ΔK_th,i corrected for near-tip residual stress in each step of the load sequence. The study confirms the crucial requirement of accounting for the combined action of the two independent and vastly different load interaction mechanisms that together induce load interaction effects in fatigue crack growth under variable-amplitude loading. It also showed that these considerations apply from a crack size as low as 0.3 mm from the origin of its natural formation.