Bioaccumulation of ionizable pharmaceuticals has been increasingly studied, with most reported aquatic tissue concentrations in field or laboratory experiments being from fish. However, higher levels of antidepressants have been observed in bivalves compared with fish from effluent-dominated and dependent surface waters. Such observations may be important for biodiversity because approximately 70% of freshwater bivalves in North America are considered to be vulnerable to extinction. Because experimental bioaccumulation information for freshwater bivalves is lacking, we examined accumulation dynamics in the freshwater pondmussel, Sagittunio subrostratus, following exposure to a model weak acid, acetaminophen (mean (±SD) = 4.9 ± 1 µg L^–1), and a model weak base, sertraline (mean (±SD) = 1.1 ± 1.1 µg L^–1) during 14-day uptake and 7-day depuration experiments. Pharmaceutical concentrations were analyzed in water and tissue using isotope dilution liquid chromatography–tandem mass spectrometry. Mussels accumulated two orders of magnitude higher concentrations of sertraline (31.7 ± 9.4 µg g^–1) compared to acetaminophen (0.3 ± 0.1 µg g^–1). Ratio and kinetic-based bioaccumulation factors of 28,836.4 (L kg^–1) and 34.9 (L kg^–1) were calculated for sertraline and for acetaminophen at 65.3 (L kg^–1) and 0.13 (L kg^–1), respectively. However, after 14 days sertraline did not reach steady-state concentrations, although it was readily eliminated by S. subrostratus. Acetaminophen rapidly reached steady-state conditions but was not depurated over a 7-day period. Future bioaccumulation studies of ionizable pharmaceuticals in freshwater bivalves appear warranted. Environ Toxicol Chem 2023;00:1–7. © 2023 SETAC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.