Objective To determine the effect of the combination of normobaric oxygen (NBO) and hyperbaric oxygen (HBO) on the serum levels of soluble intercellular adhesion molecule-1 (sICAM-1), soluble E-selectin (sE-selectin, sES) and matrix metalloproteinase-9 (MMP-9) in the patients with acute cerebral infarction. Methods A total of 168 patients with acute cerebral infarction within 24 h after onset hospitalized in our department from December 2011 to March 2014 were enrolled in this study as acute cerebral ischemia group. They were prospectively and randomly divided into 3 subgroups, that is, routine treatment subgroup, HBO subgroup and NBO+HBO subgroups. Their serum levels of sICAM-1, sES and MMP-9 were measured by enzyme-linked immunosorbent assay (ELISA) before and at 10d after treatment. The National Institutes of Health Stroke Scale (NIHSS) was employed to assess their neurological defects. The other 50 practical health persons were enrolled as control group. Results After 10 days’ treatment, the serum levels of sICAM-1, sES and MMP-9 were significantly decreased in all 3 treatment groups. (t＝8.754?11.351，P＜0.01), with those of HBO and NBO+HBO subgroups obviously lower than the routine group (t＝2.237?4.162, P＜0.05 or 0.01). Compared with the HBO subgroup, these levels were more significantly decreased in the NBO+HBO subgroup (t＝2.141?2.366, P＜0.01). The HBO and NBO+HBO subgroups had markedly lower NIHSS scores than the routine subgroup at 10d after treatment (t＝5.367, P＜0.01; t＝9.943, P＜0.01), and the scores of the NBO+HBO subgroup were more significantly decreased than that of HBO subgroup (t＝2.827, P＜0.01). Conclusion The combined therapy of NBO+HBO is superior to HBO monotheray in the inhibition of serum sICAM-1, sES and MMP-9 levels, and improves the clinical prognosis of the patients with acute cerebral infarction.