PURPOSE: To survey the prevalence and clinical and genetic characteristics of pachydrusen in eyes with central serous chorioretinopathy (CSC) and those of Japanese individuals in the general population. DESIGN: A prospective observational cohort study. PARTICIPANTS: A total of 1037 Japanese patients were included in this study; among which, 307 patients (614 eyes) had treatment-naïve CSC without choroidal neovascularization in either eye, while 730 individuals (1640 eyes) were general Japanese individuals without explicit ocular diseases. METHODS: Pachydrusen were detected using color fundus photography and subfoveal choroidal thickness was measured using optical coherence tomography. Genotypic distributions of three single nucleotide polymorphisms, ARMS2 A69S, CFH I62V and CFH Y402H, were evaluated. MAIN OUTCOME MEASURES: Prevalence of pachydrusen and association with choroidal thickness RESULTS: The prevalence of pachydrusen was significantly higher among CSC patients than that among general individuals (40.1% vs. 15.6%, P<0.001).Individuals with pachydrusen, in either group, were significantly older than those without pachydrusen (CSC patients: 62.1 vs. 48.8 years, P<0.001; general individuals: 70.3 vs. 51.9 years, P<0.001). There was no significant difference in subfoveal choroidal thickness between those with and without pachydrusen (CSC patients: 370 μm vs. 375 μm P=0.574, general individuals: 297 μm vs. 303 μm, P=0.521). However, after adjusting for age, sex, and refractive error, the subfoveal choroidal thickness was notably thicker in individuals with pachydrusen than that in individuals without pachydrusen, in both groups (P = 0.003, P=0.013, respectively). There was no significant difference in genotype distributions between CSC patients with pachydrusen and those without it; whereas, the T allele frequency of ARMS2 A69S was higher in general individuals with pachydrusen than that in general individuals without pachydrusen (42.2% vs. 33.9%; P<0.001, OR: 1.86, adjusted for age, sex, and choroidal thickness). The A allele frequency of CFH I62V was not significantly different between those with and without pachydrusen. CONCLUSIONS: Pachydrusen was more frequently observed in CSC patients compared to individuals of the general population. In both groups, pachydrusen was associated with a thicker choroid, suggesting that pachydrusen should be considered as a significant sign of pachychoroid.