Background: Hypoxia inducible factor 1(HIF-1) and microRNAs (miRNAs) regulate transcriptional activities and contribute in several biological processes such as oxygen homeostasis, cell growth, progression and apoptosis that are important in lung and upper aero-digestive tract (UADT) cancer etiology and outcomes. Nonetheless, there are few published studies of the relationship between HIF-1 and miRNA gene polymorphisms and susceptibility and survival of lung cancer or UADT cancers. Methods: 1,212 cancer patients (611 lung, 303 oral, 100 pharyngeal, 90 laryngeal, and 108 esophageal) and 1040 population controls were included and the cases were followed for a median duration of 11 years. We genotyped 18 single nucleotide polymorphisms (SNPs) using Fluidigm Dynamic 96.96 Array Assay--two from HIF-1, seven from the miRNA biogenesis pathway, two from hypoxia regulated miRNAs and seven from miRNA target genes--and investigated their associations with lung and UADT cancer risk with logistic regression and survival using Cox regression. We explored interactions between selected SNPs and established environmental risk factors. A semi-Bayesian shrinkage approach was used to reduce the potential false positive findings caused by multiple comparisons and small sample sizes. Results: The minor allele carriers CT+TT (vs. CC) of RAN rs14035 was associated with lung cancer development (posterior aOR=1.28, 95% posterior limits=1.00, 1.63), especially with non-small cell lung cancer (NSCLC); and associated with esophageal squamous carcinoma (SQC) susceptibility (posterior aOR=1.81, 95% posterior limits=1.07, 3.07). It was inversely associated with NSCLC death (posterior aHR=0.74, 95% posterior limits=0.59, 0.93). The minor allele carriers AC+CC (vs. AA) of XPO5 rs11077 presented inverse association with UADT cancer risk (posterior aOR=0.75, 95% posterior limits=0.58, 0.96), especially with UADT SQC and oral and oropharyngeal SQC; and its minor homozygote CC (vs. AA+AC) was inversely related to lung cancer mortality (posterior aHR=0.67, 95% posterior limits=0.51, 0.89), which was pronounced in NSCLC. The minor allele carriers CG+GG (vs. CC) of GEMIN4 rs2740348 were inversely related to UADT SQC susceptibility (posterior aOR=0.75, 95% posterior limits=0.57, 1.00) and associated with increased mortality of lung cancer (posterior aHR=1.28, 95% posterior limits =1.01, 1.62). In the Caucasian-only population, we repeatedly observed the inverse association between XPO5 rs11077 CC (vs. AA+AC) and lung cancer mortality; and the association between GEMIN4 rs2740348 CG+GG (vs. CC) and lung cancer death. Conclusion: Our findings suggested that single nucleotide polymorphisms (SNPs) of miRNA processing and maturation relevant genes played an important role in cancer development and progression; due to the population heterogeneity, their influence in the cancer pathophysiology need further investigations.