In routine brain DW-EPI with SENSE, the pseudo-lesion artifact due to residual aliasing of eyeball has been previously reported. We have found that the incidence of pseudo-lesion artifact was over 50% when performing double-oblique imaging on stroke patients. The possible cause is highly likely related to inference between residual Nyquist ghost and unfolding process in SENSE reconstruction. In this study, we propose a self-reference method to effectively remove pseudo-lesion artifact in double-oblique DW-EPI using virtual coil acquisition and multiplexed sensitivity encoding (MUSE). Our proposed method reveals higher image quality, better SNR performance, and lower artifact level than conventional SENSE reconstruction.