Vascular endothelial growth factor (VEGF) is a potent proangiogenic factor. Several single nucleotide polymorphisms (SNPs) in the VEGF gene with influence on VEGF expression have been described. In multiple myeloma, VEGF stimulates angiogenesis which is correlated with disease progression and prognosis. In this study, we evaluated the association between genetic variations in the VEGF gene in patients with multiple myeloma and time to treatment failure (TTF) after high-dose melphalan and stem cell support (HDT), overall survival (OS) and efficacy of the anti-angiogenic drug thalidomide. Retrospectively, the SNPs −2,578C>A (rs699947), −460C>T (rs833061), +405G>C (rs2010963) and +936C>T (rs3025039) in the VEGF gene were examined in 348 patients with newly diagnosed multiple myeloma initially treated with HDT, where 176 patients were treated with thalidomide at relapse. None of the examined geno- or haplotypes was associated with differences in TTF after initial therapy or OS. A possible relation between the haplotype −2,578A/−460C/+405G (ACG) and effect of thalidomide was seen. Patients with no copies of the haplotype ACG had a longer time to next treatment than patients with one or two copies of the haplotype ACG, median 13.7 months vs. 9.2 months, p = 0.007. In conclusion, the haplotype ACG in the VEGF gene may influence the efficacy of thalidomide in multiple myeloma. Further analyses are needed to confirm these findings and get insight into the functional effect of these polymorphisms, so in the future we may be able to select multiple myeloma patients who especially will benefit from treatment with thalidomide.