MiR-146a has 224 potential mRNA binding targets, including the cancer susceptibility gene RNASEL. Ribonuclease L is an interferon-activated ribonuclease, which degrades cellular and viral RNA upon activation. Inducing apoptosis in infected cells, prior to a full immune response. RNASEL is maintained at very low levels in the cell and its regulation is unclear, but may include miRNA suppression of its transcript and targeting of RNASEL by a miRNA, such as miR-146a, would serve to reduce cellular RNASEL levels. The RNASEL rs486907 Arg to Gln variant has 3-fold reduced enzyme activity, which could enhance virus susceptibility, diminish control of cellular RNA levels, impair the cellular stress response, or induce apoptosis. While under normal conditions RNASEL has tumor suppressive and anti-proliferative functions, RNASEL variants, including the common rs486907 variant, have been associated with risk of a number of cancers, i.e. prostate, colorectal and pancreatic cancer, and overall risk of cancer in individuals of African descent. To examine the effect of genetic variation in key immune Tubacin components on NMSC susceptibility. we investigated the impact of the MIR146A SNP rs2910164 on NMSC risk, and potential interaction with one of its putative targets RNASEL as part of a large population-based, case-control study of BCC and SCC in New Hampshire. In our population-based, case-control study of BCC and SCC, we found evidence of interacting effects of common variants in two genes involved in aspects of inflammation and immunity, RNASEL and MIR146A, on risk of NMSCs. While neither of these variants appeared to affect risk of BCC or SCC when considered singly in the entire population, gender-specific associations were observed, i.e. significant reduction in risk of BCC in women who carried the MIR146A variant C-allele, and a borderline reduction in risk of SCC in men who carried the RNASEL variant A-allele. This is consistent with our prior work indicating gender-specific immunogenetic risk effects for NMSCs, which reported that while skin type and lifetime number of sunburns were important risk factors for SCC and BCC in both men and women, the relative contribution of genetic variants involved in UV-induced immunosuppression to risk of SCC and BCC vary by sex. The rs486907 RNASEL variant has been associated with increased risk of several cancers. This Arg to Gln variant has been shown to inhibit dimerization of RNASEL into its active form, resulting in a 3-fold reduction in enzyme activity that strongly affects its endonuclease capacity and thus its pro-apoptotic activity. However, there are inconsistencies across studies with regard to risk direction for rs486907. Studies of sporadic U0126 prostate cancers have shown that the variant A allele of rs486907 may be associated with lower grade tumors, as assessed by Gleason score. It is possible that the reduction in activity associated with rs486907 may have differential effects in various tissue contexts, including tumor types, and when found in combination with other genetic variants, such as MIR146A rs2910164. RNASEL plays a significant role in viral clearance and it has been suggested that variation in RNASEL may alter risk of viralassociated cancers, such as head and neck squamous cell carcinoma and cervical cancer.