Human exposure to poly- and perfluoroalkyl substances (PFASs) is widespread and has received considerable attention in recent years due to their link with adverse health outcomes, including bone health. Nevertheless, no earlier studies have reported serum PFAS concentrations, and their association with incident osteoporosis in populations in Saudi Arabia. In this clinical case-control study, serum samples collected from 208 individuals (n = 100 cases and n = 108 controls) aged 40-89 years from Jeddah, Saudi Arabia, were analyzed for 17 PFASs. Unconditional logistic regression was used to calculate odds ratios (ORs) for association between serum PFAS concentrations and osteoporosis, stratified by gender, age, serum calcium and vitamin D, previous history of fractures and thyroid disorders. Perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), perfluorobutanoic acid (PFBA), perfluorononanoic acid (PFNA), perfluorohexane sulfonic acid (PFHxS), perfluoro-n-pentanoic acid (PFPeA) and perfluoroundecanoic acid (PFUnDA) were detected in >80% of serum samples analyzed. PFOS (overall median concentration: 5.08 ng/mL), PFHxS (1.49 ng/mL), PFOA (1.33 ng/mL) and PFNA (0.55 ng/mL) accounted for 94% and 80% of the total serum PFASs concentrations in cases and controls, respectively. Serum PFOA, PFNA and PFUnDA concentrations increased with age in Saudi women. Results from the crude models showed that individuals in the 2nd, 3rd and 4th quartiles of serum PFAS concentrations had 2.3-96-fold increase in odds of diagnosis for osteoporosis compared with those in the 1st quartile (rank order: PFUnDA > PFOA > PFNA > PFOS > PFHxS). Our results suggest that exposure to PFOA, PFOS, PFNA, PFHxS and PFUnDA was associated with osteoporosis in this sample of adult Saudi population.Copyright © 2020 Elsevier Inc. All rights reserved.