Vascular endothelial growth factor (VEGF) is an important regulator of angiogenesis and vascular permeability. Increased serum VEGF concentrations (S-VEGF) have been found in patients with various types of human cancer, including cancer of the lung. However, the clinical and prognostic significance of S-VEGF in cancer is unknown. We measured S-VEGF, using enzyme-linked immunosorbent assay, in sera taken from 68 untreated patients with small-cell lung cancer (SCLC) at the time of diagnosis. The patients were treated with 6 cycles of cisplatin and etoposide, and were randomly assigned to receive recombinant interferon, leukocyte interferon or neither. S-VEGF ranged from 70 to 1738 pg/ml (mean, 527 pg/ml). The patients who achieved partial or complete response to treatment had lower pre-treatment S-VEGF than the non-responding patients (p = 0.0083, Mann-Whitney test). High (>527 pg/ml) S-VEGF was associated with poor survival (p = 0.012, Log Rank Test), and all 3-year survivors had lower than mean pre-treatment S-VEGF. In a multivariate analysis, S-VEGF and stage were the only independent prognostic factors, and the estimated 3-year survival of the patients with limited stage disease and low pretreatment S-VEGF (n = 17, 25% of all patients) was 41% (p = 0.0055, log rank test). These data show that high pretreatment S-VEGF is associated with poor response to treatment and unfavourable survival in patients with SCLC treated with combination chemotherapy with or without interferon.