ABSTRACT This study was to explore mechanism of α2-macroglobulin (α2 MG) against oxidative stress and promote cell proliferation in the process of intervertebral disc degeneration (IDD). Nucleus pulposus cells extracted from the pathological tissues of IDD patients were treated with different concentrations of α2 MG (0, 0.1, 0.2, 0.4, 0.8, and 1 mg/mL), and were grouped into Group Z, Group A, Group B, Group C, Group D, and Group E, respectively. The cell proliferation, cell morphology, superoxide anion (SOA) content, and superoxide dismutase (SOD) activity were detected 1, 3, 5, and 7 days after the culture. The results showed that with the increase of α2 MG concentration and culture time, the O2- content in nucleus pulposus cells gradually decreased (P < 0.05); the viability of the nucleus pulposus cells gradually increased after 1, 3, 5, and 7 days after culture, and the viabilities in the groups C, D, and E with α2 MG concentrations of 0.4 mg/mL, 0.8 mg/mL, and 1 mg/mL were much higher in contrast to viability in group Z (P < 0.05). Electrophoresis results showed that the relative expression of α-smooth muscle actin (α-SMA) protein in groups A, B, C, D, and E were 0.57, 0.66, 0.68, 0.77, and 0.84, respectively, all showing remarkable differences compared with the expression in group Z (P < 0.05). In summary, α2 MG can play a very good role in preventing oxidative stress and promoting cell proliferation in the process of IDD.