Individuals in a given environment contaminated with arsenic have different susceptibilities to disease, which may be related to arsenic metabolism, age, gender, genetics and other factors. This study recruited 850 subjects, including 331 cases and 519 controls, from populations exposed to high levels of arsenic in drinking water in northwest China. Genotypes were determined using a custom-by-design 48-Plex SNPscanTM kit. The results indicated that subjects who carried at least one C allele for GSTO1 rs11191979 polymorphism, at least one A allele for GSTO1 rs2164624, at least one A allele for GSTO1 rs4925, the AG genotype for GSTO2 rs156697, the AG genotype or at least one G allele for GSTO2 rs2297235 or the GG genotype or at least one G allele for PNP rs3790064 had an increased risk of arsenic-related skin lesions. In addition, the haplotype CT between rs4925 and rs11191979 appeared to confer a high risk of arsenic-included skin lesions (OR = 1.377, 95% CI = 1.03-1.84), as did the haplotype GCG among rs156697, rs157077 and rs2297235 (OR = 2.197, 95% CI = 1.08-4.44). The results showed that the variants of GSTO1, GSTO2 and PNP render the susceptible toward developing arsenic-induced skin lesions in individuals exposed to high-dose inorganic arsenic in northwest China.