BACKGROUND: The vascular endothelial growth factor (VEGF) is involved in tumorigenesis of the upper aerodigestive tract. Different single nucleotide polymorphisms (SNPs) turn the regulation of the VEGF gene into a highly complex process, particularly influenced by exogenic factors like cigarette smoke (CSE). Analysis of the SNP- and CSE-dependent VEGF-gene regulation can help to improve antiangiogenic therapies and prognosis. Therefore, the aim of this study was to analyse the influence of CSE on the SNP-dependent regulation of the VEGF-gene in vitro. METHODS: Human alveolar epithelial-like type-II cells (A549) were transfected with different SNPs and incubated with CSE. SNP- and CSE-dependent VEGF-promoter activity and mRNA stability was measured using qRT-PCR and Western blot analysis. RESULTS: Transfection with SNP -460 (ATC) and incubation with 10% CSE resulted in +19% elevated VEGF-promoter activity (P < 0.05). Transfection with SNP -2578/-460 (CTC) and 10% CSE incubation resulted in a 14% reduction of VEGF-promoter activity (P < 0.05). Regarding mRNA stability, transfection with SNP +936 T allele led to half-life of 1.11 hours, which decreased to 0.2 hours after incubation with CSE. In contrast, on protein level SNP +936 T transfection showed a not significant increase up to 176% (P > 0.05), while incubation with CSE led to a significant decrease to 61% (P = 0.002). CONCLUSION: Transcriptional regulation of the VEGF gene by SNP -460 (ATC) in combination with CSE represents a mechanism for elevated VEGF expression and may be associated with a worse prognosis. The influence of +SNP 936 on mRNA stability may be responsible for regulation of VEGF plasma levels.