Increasing evidence has demonstrated that changes in plasma nuclear matrix proteins are specific markers of cancer. Furthermore, proteomic analysis has revealed that calponin-h2 is upregulated in human breast cancer tissue, but is absent in healthy and benign controls. However, the roles of levels of plasma calponin-h2 in the diagnosis of breast cancer and its association with clinicopathological parameters remain to be elucidated. In the present study, the plasma levels of calponin-h2 in patients with breast cancer, benign breast disease and in healthy controls were examined using an enzyme-linked immunosorbent assay. The expression levels of calponin-h2 in invasive breast cancer and normal breast tissues were measured using immunohistochemistry. Statistical analyses examined the association between the levels of plasma calponin-h2 and clinicopathological parameters. The results demonstrated that the plasma level of calponin-h2 in breast cancer was significantly higher than those in the healthy control and benign breast disease groups (P<0.05). The combination of calponin-h2, carcinoembryonic antigen, carbohydrate antigen 15-3 improved the diagnosis of breast cancer. The plasma levels of calponin-h2 PR-breast cancers was significantly higher, compared with PR+ breast cancers (P=0.033), and the plasma levels of calponin-h2 in patients with breast cancer aged >50 years was significantly higher than in patients ≤ 50 years of age (P=0.001). No association was found between the level of plasma calponin-h2 and other clinicopathological parameters of breast cancer. Taken together, these results indicated that calponin-h2 may be a useful marker of breast cancer.