Patients with primary non-melanoma skin cancers (NMSCs) tend to develop these cancers at multiple independent sites. We examined the genetic factors in the development of multiple NMSCs among Caucasian women with 28 years of follow-up. We initially evaluated 19 SNPs in nine pigmentation genes with the number of NMSCs in 492 cases and 619 controls without a history of NMSC. We found nominal significant associations between two ASIP gene-related SNPs, rs1885120 and rs910873, and an ASIP haplotype (AH) (rs4911414 allele T and rs1015362 allele G) and an increased number of NMSCs, with p-values of 0.008, 0.01, and 0.01, respectively. We further evaluated these two SNPs and AH haplotype in three data sets. In a joint analysis with 1,507 cases and 4,335 controls, AH haplotype was independently associated with the number of NMSCs with odds ratio (OR) (95% confidence interval (CI)) of 1.45(1.25-1.68) (p-value = 6.2E-07). The AH haplotype was associated with an increased risk of developing one NMSC (OR 1.32; 95% CI, 1.07-1.63). The OR increased to 1.45(1.18-1.78) for those with 2-4 NMSCs and 1.84(1.34-2.53) for those with at least five. The findings suggest that ASIP locus is associated with the number of NMSCs.