Abstract: To improve the seismic resilience and safety reserve, an innovative self-centering prefabricated frame structure (ISCPFS) with composite concrete-filled steel tubular columns was proposed. The structure dissipated energy via web friction devices at the beam ends and achieved self-centering of beam-column joints and column bases using the unbonded prestressed steel strand. Two full-scale, single-layer, single-span prefabricated frame specimens were designed and tested: in the ISCPFS, the steel strands were exclusively placed within the beam, while in the ordinary self-centering prefabricated frame structure (OSCPFS), the steel strands were arranged across the span. Quasi-static tests were conducted to investigate the failure mode, hysteretic behavior, energy dissipation capacity and, self-resetting capacity. The results indicated that the beam and the column remained elastic during loading, primarily dissipating energy through the web plate friction. At a drift ratio of 3%, the prestressed steel strands remained elastic, and their rebound effect shut the openings at the beam-column joints and the column bases. The self-resetting coefficients of ISCPFS and OSCPFS were 93.1% and 90.7%, respectively, indicating high post-earthquake repairability. Compared with OSCPFS, ISCPFS exhibited a 5.6% increase in load-bearing capacity and a 16.8% improvement in ductility, while the prestress loss in the steel strands was reduced by 40.6%. The finite element model established can effectively simulate the hysteresis behavior of the ISCPFS under low-cycle reciprocating loads. The results of parameter analysis showed that the critical rotation load, rotational stiffness and, ultimate bearing capacity of the structure increased with the increase of the initial prestress of the beam and of the column steel strands, and of the initial torque of the bolts in the friction device.