Background: Brain metastases (BM) in colorectal cancer (CRC) are rare, developing in only 0.3-9% of the patients, and considered a late-stage manifestation of the disease. The aim of this study was to investigate whether genetic variants of genes from integrin, invasion- and adhesion-mediating, angiogenic and tumor suppressing pathways, involved in overcoming the blood-brain barrier are associated with outcome. Methods: Genomic DNA was extracted from formalin-fixed paraffin embedded resected BM from 70 patients with histologically proven CRC. Single nucleotide polymorphisms (SNP) in seven genes (CXCR4, MMP9, ST6GALNAC5, ITGAV, ITGB1, ITGB3, KLF4) were analyzed by direct Sanger DNA sequencing and evaluated for association with overall survival (OS) from resection of BM. Only SNPs with an allele frequency of ≥10% were analyzed. Results: In univariate analysis, rs17577 (MMP9) and rs4642 (ITGB3) showed a significant difference in OS [(G/G 7.4 months, G/A 5.1 months; HR (95% CI) 1.83 (0.95-3.53), P=0.044) and (A/A or A/G 8.0 months, G/G 4.3 months; HR (95% CI) 2.31 (1.08-4.93), P=0.014), respectively]. In multivariate analysis adjusted for baseline characteristics (primary tumor site, age at diagnosis of CRC, BM location, Karnofsky performance status), rs2236599 (KLF4), rs10171481 (ITGAV), rs1883778 (ST6GALNAC5), and rs2680880 (CXCR4) were significant in OS [(G/G 7.4 months, G/A or A/A 4.8 months; HR (95% CI) 2.12 (1.01-4.45), P=0.048), (A/A or A/G 5.3 months, G/G 15.5 months; HR (95% CI) 0.39 (0.18-0.85), P=0.018), (G/G 4.6 months, G/A or A/A 9.4 months; HR (95% CI) 0.53 (0.30-0.93), P=0.028) and (A/A 6.4 months, A/T 9.3 months, T/T 4.6 months; HR (95% CI) 0.45 (0.22-0.89) and 1.54 (0.75-3.15), P=0.005), respectively]. Recursive partitioning analyses revealed that rs4642 is the dominant SNP predicting OS. Conclusions: This study suggests for the first time a prognostic effect of the genetic variations within genes involved in the blood-brain barrier breach. Further analyses are needed to confirm these findings.