BACKGROUND Numerous studies have confirmed that hyperbaric oxygen (HBO) in combination with radiotherapy or chemotherapy may increase the efficacy of radiotherapy or chemotherapy in patients with glioma. However, whether HBO therapy alone may inhibit or promote the growth of malignant tumors remains controversial. This study aimed to investigate the effect of HBO on the growth of glioma in rats, and the impact of HBO on the expression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1-alpha (HIF-1α), angiogenesis, and apoptosis of glioma cells. METHODS Male Sprague-Dawley rats were treated with or without HBO after glioma cell inoculation and followed for up to 16 days postinoculation. Rats were randomized to receive bilateral forelimb function tests (n = 20 per group) and head magnetic resonance imaging (n = 5 per group). Differences between HBO and control groups were tested using 2-sample independent t-tests and changes over time within treatment groups were analyzed using a repeated measurement analysis of variance with Bonferroni correction. The effect of HBO on the expression of VEGF, HIF-1α, von Willebrand factor, angiogenesis, and tumor cell apoptosis were also examined (n = 5 per group). RESULTS Forelimb function scores were reduced in both HBO-treated and control groups. HBO-treated rats had significantly larger tumor volume and more water in the cerebellum compared with control rats. The intratumoral expression of VEGF was significantly higher in HBO-treated rats compared with control rats (23.2% vs. 13.3%, P = 0.002). HIF-1α was significantly increased in HBO-treated rats compared with controls in the expression of both intratumoral (72.7% vs. 54.9%, P = 0.001) and peritumoral (2.6% vs. 1.9%, P = 0.003) cells. The intratumoral microvessel density (MVD) was significantly higher in the HBO group (15.6 vessels/field vs. 4.4 vessels/field, P < 0.001), and the peritumoral MVD was not significantly different between the two groups (P > 0.05). Apoptosis was significantly lower in HBO-treated rats compared with controls (44.4% vs. 82.8% for intratumoral; 10.1% vs. 77.5% for peritumoral, both P < 0.001). CONCLUSIONS The current results demonstrate that HBO alone may promote tumor growth, and is therefore not suitable to treat patients with gliomas with neurological deficits or disorders with HBO alone. If HBO must be used as a mean of rehabilitation, it is recommended that HBO should be combined with radiotherapy or chemotherapy.