Background: The newly discovered metastasis-associated in colon cancer-1 (MACC1) gene is a key regulator of the HGH/met pathway. Deregulation of HGH/met signalling is reported as prognostic marker for early stage invasion, tumorigenesis, and metastasis. High expression levels of MACC1 have been associated with colon cancer metastasis and reduced 5-year survival. Potential links between the genetic diversity of the MACC1 locus and overall survival are unknown. We therefore investigated the association between MACC1 tagging single nucleotide polymorphisms (SNPs) and overall survival in a large cohort of colorectal cancer patients. Methods: The study included 319 subjects with histopathologically proven colorectal cancer at the Academic Teaching Hospital Feldkirch, Austria. Survival data were provided by the federal agency for statistics in Austria. Genomic DNA was isolated from formalin-fixed paraffin-embedded specimens; six tagging SNPs (rs1990172, rs3114446, rs10275612, rs3095007, rs3095009, and rs7780032) capturing the common variants of the MACC1 locus were genotyped by SNaPshot assays. Results: Over a mean follow up period of 4.3 (± 1.0) years, 73 deaths were recorded. Carriers of the rare allele of SNP rs1990172 showed a significantly decreased overall survival (HR = 1.73 [1.08 –2.77]; p = 0.023). Multivariate analysis adjusted for age, gender, and UICC tumor stage confirmed this result (HR = 1.82 [1.13 –2.94]; p = 0.013). Other investigated genetic variants of the MACC1 gene were not significantly associated with overall survival (p-values > 0.05). Conclusions: For the first time, our study investigates the influence of MACC1 tagging polymorphisms on overall survival suggesting SNP rs1990172 as a predictor for reduced overall survival in colorectal cancer patients. Further studies will be required to validate our findings.