Disseminated coccidioidomycosis (DCM) is caused by Coccidioides, pathogenic fungi endemic to the Southwestern United States and Mexico. While the majority of those infected have minor symptoms or remain asymptomatic, illness requiring medical attention occurs in approximately 30%, with <1% developing extrapulmonary dissemination. To address why some individuals allow dissemination, we performed whole-exome sequencing on an exploratory cohort of 67 DCM patients. Using standard genetic analysis for identification of novel or rare Mendelian mutations only two patients were identified, both with STAT3 premature termination codons causing haploinsufficiency. Since Coccidioides are geographically isolated, I explored the possibility that dissemination could be a combination of more common genetic variants plus exposure. Defects in sensing and response to -glucan, the major component of Coccidioides cell wall, were seen in 34/67 (50.7%) cases. Damaging variants in CLEC7A, encoding DECTIN-1, (n=14) and PLCG2 (n=11) were associated with impaired production of -glucan-stimulated TNF from peripheral blood mononuclear cells compared to healthy controls (P<0.005). Using ancestry-matched controls, damaging CLEC7A and PLCG2 variants were over-represented in DCM (P=0.0206, P=0.015, respectively) including CLEC7A Y238* (P=0.0105) and PLCG2 R268W (P=0.0025). A validation cohort of 111 DCM patients confirmed over-representation of the specific variants, PLCG2 R268W (P=0.0276), CLEC7A I223S (P=0.044), and CLEC7A Y238* (P=0.0656). Lastly, I identified a novel pathway of pulmonary-epithelial fungal recognition by DECTIN-1 leading to activation of the NADPH oxidase complex, DUOX1/DUOXA1. Stimulation with a DECTIN-1 agonist induced DUOX1/DUOXA1-derived H2O2 in transfected cells. Heterozygous DUOX1 or DUOXA1 variants which impaired H2O2 production were overrepresented in discovery and validation cohorts. Together these studies highlight the importance of fungal recognition and response for control of infections. Patients with DCM have impaired -glucan sensing or response affecting TNF and H2O2 production. Impaired Coccidioides recognition and decreased cellular response are associated with disseminated coccidioidomycosis.