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Although postmenopausal (post-M) women have behavioral and biological risk factors for HIV infection, the activity of preexposure prophylaxis (PrEP) agents in older adults has not been well studied.We used an ex-vivo approach to compare the tissue concentrations of tenofovir (TFV) diphosphate (TFVdp) and emtricitabine (FTC) triphosphate (FTCtp) in cervical tissues from premenopausal (pre-M) and post-M women.Cervical explants from 16 pre-M and 11 post-M women were incubated in 10–300 μg/ml TFV or FTC for 24 h. Explants were then snap frozen in liquid nitrogen and stored until analysis. TFVdp and FTCtp were quantified using tandem liquid chromatography–mass spectrometry.Active metabolite concentrations of TFVdp were more than nine-fold lower in post-M explants (P < 0.05). The percentage of TFV converted to TFVdp in pre-M explants was 0.0038 [below the limit of quantification (BLQ)-0.5886] compared with 0.0004 (BLQ-0.0706) in post-M explants. The majority of FTCtp concentrations were BLQ. For both TFVdp and FTCtp, there was a trend for more unquantifiable concentrations in post-M vs. pre-M (TFV: 38 vs. 21%, P = 0.2; FTC: 71 vs. 52%, P = 0.2).These findings could have implications in the use of nucleotide-based PrEP strategies targeted to older women. If validated in vivo, lower exposures of active nucleoside/tide metabolites could mean post-M women need higher doses of TFV-based PrEP to achieve protective efficacy.