Serum neuron‐specific enolase (NSE) was measured in 61 children at diagnosis with all stages of neuroblastoma. The median serum values for Stages I, II, III, IV, and IV‐S were 13, 23, 40, 214, and 40 ng/ ml, respectively. Mean serum levels were different between groups I versus IV, (P = 0.0004) II versus IV (P = 0.0001) and IV‐S versus IV (P = 0.004). The prognostic value of serum NSE for disease‐free survival was determined in 54 patients at risk for relapse 2 or more years after diagnosis. The disease‐free survival rate of all patients with levels of less than 100 ng/ml was 27/34 (79%), whereas it was 2/20 (10%) for those with higher levels. In 28 patients with lower stage disease and a good prognosis (Stages I, II, and IV‐S) NSE levels were not predictive of relapse. Only 1 of these 28 patients had a raised level (>100 ng/ml) and survived without relapse, whereas 4 patients who relapsed had serum NSE less than 100 ng/ ml at diagnosis. In patients with Stages III and IV disease, a raised serum NSE level was associated with poor outcome: only 1/19 (5%) survived with NSE levels > 100 ng/ml, whereas survival was 5/8 (63%) with values below 100 ng/ml. Serial samples were analyzed on 17 patients; all 8 patients with initial NSE levels > 100 ng/ml achieved near normal levels during remission (median, 21 ng/ml). However, in only 4/10 patients studied at time of relapse, did the levels rise coincident with relapse. The sera of 47 patients with other forms of cancer and 19 siblings of cancer patients were at or near the normal limits (0–15 ng/ ml), with three exceptions: acute lymphoblastic leukemia (286 ng/ml), hepatoblastoma (176 ng/ml), and primitive neuroectodermal tumor (105 ng/ml). Serum NSE is a useful marker for patients with advanced neuroblastoma in whom elevated levels were associated with a poor outcome; the raised NSE levels returned to near normal after therapy. In patients with Stage IV‐S disease serum NSE levels were significantly lower than those in Stage IV despite their extensive tumor burden. Serum NSE estimation may confirm Stage IV‐S status and suggest a more benign clinical course.