Focal segmental glomerulosclerosis (FSGS) and collapsing glomerulopathy are common causes of nephrotic syndrome. Variants in over 20 genes have been associated with these podocyte diseases, including genes critical for mitochondrial function. One such gene, PDSS2, is required for synthesis of the decaprenyl tail of coenzyme Q10 in humans. The mouse gene Pdss2 is mutated in the kd/kd mouse model of collapsing glomerulopathy. We examined the hypothesis that human PDSS2 polymorphisms are associated with podocyte diseases. We genotyped 377 cases with primary FSGS or collapsing glomerulopathy, together with 900 controls, for nine single nucleotide polymorphisms (SNPs) in the PDSS2 gene in a case-control study. Subjects included 247 African American (AA) and 130 European American (EA) cases, and 641 AA and 259 EA controls. Among EAs, a pair of proxy SNPs was significantly associated with podocyte disease, and patients homozygous for one PDSS2 haplotype had a strongly increased risk for podocyte disease. By contrast, the distribution of PDSS2 genotypes and haplotypes were similar in AA cases and controls. Thus, a PDSS2 haplotype, which has a frequency of 13% in the EA control population and a homozygote frequency of 1.2%, is associated with a significantly increased risk for FSGS and collapsing glomerulopathy in EA. Lymphoblastoid cell lines (LCLs) from FSGS patients had significantly less coenzyme Q10 than cell lines from controls; unexpectedly this finding was independent of PDSS2 haplotype. These results suggest that FSGS patients have coenzyme Q10 deficiency, and that this deficiency is manifested in patient-derived LCLs.