Objective To investigate the correlation between disease progression and expression levels of endothelial dysfunction (ED)-related factors (homocysteine[Hcy], tumor necrosis factor-alpha[TNF-α], interleukin-6[IL-6], and C-reactive protein[CRP]) in patients with cerebral small vessel disease (CSVD).Methods A total of 60 patients who were diagnosed with CSVD in our department from June 2016 to September 2017 were enrolled as study subjects. All the patients underwent a cerebral MRI examination. The peripheral blood samples of the patients were collected and tested for expression levels of ED-related factors (Hcy, TNF-α, IL-6, and CRP) using ELISA. All the patients enrolled were followed up for 1 year, during which cerebral MRI examinations were regularly performed. According to the follow-up results, the patients were divided into progression group and progression-free group. The two groups were compared for differences in the expression levels of serum Hcy, TNF-α, IL-6, and CRP. Meanwhile, the correlation between these indices and CSVD progression was analyzed.Results Among the 60 patients, 38 had disease progression, and 22 had no disease progression. Compared with the progression-free group, the progression group had significantly higher levels of Hcy (11.35±5.41 vs 17.62±7.23, P=0.007) and IL-6 (8.48±4.67 vs 17.46±6.97, P=0.001), but there were no significant differences in the expression levels of TNF-α and CRP between the two groups. A Spearman rank correlation analysis revealed that disease progression was correlated with the expression levels of Hcy (r=0.587, P=0.015) and IL-6 (r=0.644, P=0.009) but not correlated with the expression levels of TNF-α and CRP in patients with CSVD.Conclusions The expression levels of ED-related factors in serum such as Hcy and IL-6 are correlated with disease progression in patients with CSVD. Therefore, measuring the expression of these factors can provide a reference for the prognosis of the disease.