Neuroblastoma is the third-most-common solid tumor of childhood. To date, no reliable blood marker for neuroblastoma has been established. The growth factor midkine is highly expressed in human carcinomas and its knockdown leads to tumor growth suppression in animal models. The present study evaluated the plasma midkine level in human neuroblastoma patients. Plasma samples were obtained from patients found through mass screening, as well as from sporadic neuroblastoma patients. The total number of cases examined was 756. Among them, prognostic information was available for 175 sporadic cases and 287 mass-screening cases. Midkine levels were significantly higher in neuroblastoma patients, including both mass-screening cases and sporadic cases, than in non-tumor controls (P < 0.0001). The midkine level was significantly correlated with the statuses of MYCN amplification, TRKA expression, ploidy, stage and age (P < 0.0001, < 0.0001, = 0.004, < 0.0001 and < 0.0001, respectively), which are known prognostic factors for neuroblastoma. There was a striking correlation between high plasma midkine level and poor prognosis (P < 0.0001). Within sporadic cases, the midkine level was also strikingly higher than in non-tumor controls (P < 0.0001), and correlated with the statuses of MYCN amplification and stage (P = 0.0005 and = 0.003, respectively). There was a significant correlation between high plasma midkine level and poor prognosis (P = 0.04). Taken N euroblastoma (NBL) is the third-most-common malignant tumor of childhood, accounting for 15% of cancer-related death. (1) In spite of an enormous amount of research devoted to curing this disease, its prognosis remains poor. NBL has several established prognostic factors, i.e. MYCN amplification, TRKA expression level, ploidy, stage and age. (1,2) Cases with tumors with an amplified MYCN gene, low TRKA expression or diploidy show poor prognosis. Cases at stage 3 or 4, or at ages older than 18 months also show poor prognosis. Since molecular fingerprints within tumor tissues, such as MYCN amplification, TRKA expression level and ploidy, require a tumor biopsy or its removal, a blood marker for NBL has long been awaited. (1,2) A blood marker would not only be useful for the initial diagnosis but would also be beneficial for the sequential monitoring of the tumor status.The growth factor midkine (MK) was originally found in embryonal carcinoma cells, and has been implicated in cancer development. (3)(4)(5) MK is highly and frequently expressed in human carcinomas, including Wilms' tumor, tumors of the digestive tract, brain tumors, urinary bladder tumors and breast tumors, whereas its expression is scarcely detected in normal adult tissues. (6-10) Strong MK expression is also detected in precancerous stages of human colorectal cancer and human prostate cancer. (11,12) Knockdown of MK expression leads to suppression of xenografted tumors of mouse colorectal cancer cells and human prostate cancer cells. (13,14) We previously reported that the plasma MK level was correlated wit...