Rho GTPases control cell division, motility, adhesion, vesicular trafficking and phagocytosis, which may affect progression and/or prognosis of cancers. Here, we investigated associations between genetic variants of Rho GTPases-related genes and cutaneous melanoma-specific survival (CMSS) by re-analyzing a published melanoma genome-wide association study (GWAS) and validating the results in another melanoma GWAS. In the single-locus analysis of 36,018 SNPs in 129 Rho-related genes, 427 SNPs were significantly associated with CMSS (P<0.050 and false-positive report probability <0.2) in the discovery dataset, and five SNPs were replicated in the validation dataset. Among these, four SNPs (i.e., RHOU rs10916352 G>C, ARHGAP22 rs3851552 T>C, ARHGAP44 rs72635537 C>T and ARHGEF10 rs7826362 A>T) were independently predictive of CMSS (a meta-analysis derived P=9.04 × 10(-4) , 9.58 × 10(-4) , 1.21 × 10(-4) and 8.47 × 10(-4) , respectively). Additionally, patients with an increasing number of unfavorable genotypes (NUGs) of these loci had markedly reduced CMSS in both discovery dataset and validation dataset (Ptrend =1.47 × 10(-7) and 3.12 × 10(-5) ). The model including the NUGs and clinical variables demonstrated a significant improvement in predicting the five-year CMSS. Moreover, rs10916352C and rs3851552C alleles were significantly associated with an increased mRNA expression levels of RHOU (P=1.8 × 10(-6) ) and ARHGAP22 (P=5.0 × 10(-6) ), respectively. These results may provide promising prognostic biomarkers for CM personalized management and treatment. This article is protected by copyright. All rights reserved.