Rapidly and randomly drifted reference frames will shorten the link distance and decrease the secure key rate of realistic quantum key distribution (QKD) systems. However, an actively or inappropriately implemented calibration scheme will increase complexity of the systems and may open security loopholes. In this article, we present a free-running reference-frame-independent (RFI) QKD scheme, where measurement events are classified into multiple slices with the same misalignment variation of reference frames and each slice performs the post-processing procedure individually. We perform the free-running RFI QKD experiment with a fiber link of 100km and the misalignment of the reference frame between Alice and Bob is varied more than 29 periods in a 50.7-hour experiment test. The average secure key rate is about 734 bps with a total loss of 31.5 dB, which achieves the state-of-art performance of the long-distance RFI QKD implementations. Our free-running RFI scheme can be efficiently adapted into the satellite-to-ground and drone based mobile communication scenarios, as it can be performed with rapidly varying reference frame and a loss more than 40 dB, where no secure key can be obtained by the original RFI scheme.