Background and Purpose-We aimed to evaluate the efficacy of remote ischemic conditioning (RIC) in patients with cerebral small-vessel disease. Methods-Thirty patients with cerebral small-vessel disease-related mild cognitive impairment were enrolled in this prospective, randomized controlled study for 1 year. Besides routine medical treatment, participants were randomized into the experimental group (n= 14) undergoing 5 cycles consisting of ischemia followed by reperfusion for 5 minutes on both upper limbs twice daily for 1 year or the control group (n= 16) who were treated with sham ischemia-reperfusion cycles. The primary outcome was the change of brain lesions, and secondary outcomes were changes of cognitive function, plasma biomarkers, and cerebral hemodynamic parameters both at baseline and at the end of 1-year follow-up. Results-Compared with pretreatment, the post-treatment white matter hyperintensities volume in the RIC group was significantly reduced (9.10 +/- 7.42 versus 6.46 +/- 6.05 cm(3); P=0.020), whereas no significant difference was observed in the sham-RIC group (8.99 +/- 6.81 versus 8.07 +/- 6.56 cm(3); P=0.085). The reduction of white matter hyperintensities volume in the RIC group was more substantial than that in sham group (-2.632 versus -0.935 cm(3); P=0.049). No significant difference was found in the change of the number of lacunes between 2 groups (0 versus 0; P=0.694). A significant treatment difference at 1 year on visuospatial and executive ability was found between the 2 groups (0.639 versus 0.191; P=0.048). RIC showed greater effects compared with sham-RIC on plasma triglyceride (-0.433 versus 0.236 mmol/L; P=0.005), total cholesterol (-0.975 versus 0.134 mmol/L; P < 0.001), low-density lipoprotein (-0.645 versus -0.029 mmol/L; P=0.034), and homocysteine (-4.737 versus -1.679 mu mol/L; P=0.044). Changes of the pulsation indices of middle cerebral arteries from the baseline to 1 year were different between the 2 groups (right: -0.075 versus 0.043; P=0.030; left: -0.085 versus 0.043; P=0.010). Conclusions-RIC seems to be potentially effective in patients with cerebral small-vessel disease in slowing cognition decline and reducing white matter hyperintensities.