Roof-to-wall-connection (RTWC) is critical in the loading path of wood-frame residential buildings, whose fatigue performance under varying wind loading is investigated in this paper. To get an insight on the wind-induced fatigue behavior at low to moderate hourly mean wind speeds and to demonstrate the effects of adhesives on the fatigue performance of RTWC, two types of fatigue experiments, namely the constant and the varying amplitude loading tests, were conducted on three RTWC configurations with and without elastomeric construction adhesives. Based on the constant amplitude loading test results, fatigue life prediction models were developed, and the reduction in the static load capacity due to cyclic loadings were estimated. Adhesives are shown to increase the endurance limit of the RTWCs, which is desirable to enhance the life-cycle performance of wood buildings. The varying amplitude loading test results indicate that buildings in non-hurricane regions are vulnerable to fatigue damage at a low-level mean wind speed. It may induce loadings above the endurance limit of the RTWCs. On the other hand, the linear Miner’s cumulative fatigue damage model can be reasonably used to predict fatigue damage of the RTWCs when subject to multi-amplitude wind loadings. Toenailed connections generally fail in a less ductile manner at a certain number of load cycles with no warnings compared to the connections with adhesives that fail in a more ductile manner. The testing results presented herein provide essential data on the hysteresis behavior and failure modes of RTWCs to facilitate future implementation of adhesives in wood constructions.