Abstract Context α-klotho is an integral membrane protein that serves as a coreceptor for fibroblast growth factor 23 (FGF23) in conjunction with cognate fibroblast growth factor receptors. Proteolytic cleavage sheds the ectodomain of α-klotho (soluble α-klotho) as an endocrine substance into blood, urine, and cerebrospinal fluid. Objective To study the relationship of soluble α-klotho to mineral metabolism in the general population with mainly preserved kidney function. Design Cross-sectional analysis of the associations between soluble α-klotho with laboratory markers of markers of mineral metabolism in a population-based cohort. Setting Three centers in Switzerland including 1128 participants. Measures Soluble full-length α-klotho levels by a specific immunoassay and markers of mineral metabolism. Results The median serum level of soluble α-klotho was 15.0 pmol/L. Multivariable analyses using α-klotho as the outcome variable revealed a sex-by-PTH interaction: In men, PTH was positively associated with α-klotho levels, whereas this association was negative in women. Plasma phosphate associated with soluble α-klotho levels in an age-dependent manner, changing from a positive association in young adults gradually to a negative association in the elderly. The decline of 1,25 (OH)2 vitamin D3 levels in parallel to the gradual impairment of kidney function was greatly attenuated in the setting of high circulating soluble α-klotho levels. Conclusions Soluble α-klotho level is associated with plasma phosphate in an age-dependent manner and with PTH in a sex-dependent manner. Furthermore, our data reveal soluble α-klotho as a modulator of 1,25 (OH)2 vitamin D3 levels in individuals with preserved renal function.