In order to study the fragility of a reinforced concrete (RC) frame structure subjected to multi-dimensional earthquakes of different-duration, 19 sets of long and short-duration ground motions are assembled by using "spectrally equivalent". Incremental dynamic analysis (IDA) is used to analyze the fragility of an RC frame structure. The IDA curve and percentile curves for two-dimensional and three-dimensional long- and short-duration ground motions are obtained. Analyzing the response of a structure subject to ground motions with different dimensions and durations using Sa(T1,0.05) as a ground motion intensity parameter, a structural seismic probability demand model is established, and different evaluation indicators are used to analyze the failure probabilities of the structure. The results show that when subjected to long-duration ground motion, the structure is more prone to collapse. Compared with two-dimensional ground motion, the effect of long-durations has a slightly advance on structural damage subjected to three-dimensional ground motion. Different fragility evaluation measures can be used to evaluate the seismic performance of the structure, which can be used in engineering design.