A differencing multiuser detection (MUD) method is proposed for multiple-input multiple-output (MIMO) direct sequence (DS) ultra-wideband (UWB) system to cope with the multiple access interference (MAI) and the computational efficiency in Nakagami fading channel. The method, which combines a multiuser-interference-cancellation-based decision feedback equalizer using error feedback filter (MIC DFE-EFF), a coefficient optimization algorithm (COA) and a differencing algorithm (DA), is termed as MIC DFE-EFF (COA) with DA for short. In the paper, the proposed MUD method is illuminated from the rudimental MIC DFE-EFF to the advanced MIC DFE-EFF (COA) with DA step by step. Firstly, the MIC DFE-EFF system performance is analyzed by minimum mean square error criterion. Secondly, the COA is investigated for optimization of each filter coefficient. Finally, the DA is introduced to reduce the computational complexity while sacrificing little performance. Simulations show a significant performance gain can be achieved by using the MIC DFE-EFF (COA) with DA detector. The proposed MIC DFE-EFF (COA) with DA improves both bit error rate performance and computational efficiency relative to DFE, DFE-EFF, parallel interference cancellation (PIC), MIC DFE-EFF and MIC DFE-EFF with DA, though it sacrifices little system performance, compared with MIC DFE-EFF (COA) without DA.