Vascular endothelial growth factor (VEGF) is a multifunctional cytokine that increases microvascular permeability and directly stimulates endothelial cell growth and angiogenesis. Recent evidence suggests that the genetic regulation of angiogenesis is also of crucial importance and that oncogenes and tumor suppressor genes can regulate it. The aim of this study was to determine the prognostic value of VEGF and its possible association with p53-gene mutation in 89 stage I-IIIa surgically treated NSCLC patients. DNA sequencing of the p53 gene (exons 5-8) showed 40 mutations (45%). Among the 89 NSCLC patients, immunoreactivity for VEGF was weakly, moderately and strongly positive in 35 (39%),36 (40%) and 18 (20%) cases, respectively. A strong, statistically significant association was found between the presence of a p53 gene mutation and expression of VEGF (P<0.001). The positive result of the p53 mutation increased the odds of observing a higher level of VEGF expression approximately 9.5 times (95% confidence interval: [3.44,25.89]). In the univariate analysis of survival, increasing levels of VEGF expression were associated with poor prognosis (P<0.001 for trend). In the multivariate analysis, after adjusting for the presence of a p53-gene mutation, gender, TNM stage and histological type, the prognostic effect of VEGF expression level was marginally non-significant (P=0.077). When the two-category quantification of the VEGF level was considered (low vs. intermediate/high), a marginally significant (P=0.024), unfavorable effect of intermediate/high levels of VEGF expression, independent of the effect of the presence of a p53-gene mutation, was found. In conclusion, we found that the p53 mutation was closely related to VEGF expression. Additionally, we observed that an intermediate/high expression of VEGF might be a useful indicator of prognosis in NSCLC. This latter conjecture, suggested by an analysis of the data, ought however, to be independently verified in further studies.