Freshwater mussels are generally underrepresented in toxicity databases used to derive water quality criteria, especially for long‐term exposures. Multiple tests were conducted to determine the chronic toxicity of sodium chloride (NaCl) or potassium chloride (KCl) to a unionid mussel (fatmucket, Lampsilis siliquoidea). Initially, a 4‐wk NaCl test and a 4‐wk KCl test were conducted starting with 2‐mo‐old mussels in water exposures with and without a thin layer of sand substrate. A feeding study was conducted later to refine test conditions for longer‐term 12‐wk exposures, and 3 chronic NaCl tests were then conducted following the refined method to assess the influence of test duration (4–12 wk) and age of organisms (starting age ∼1 wk to 2 mo) on mussel sensitivity. Biomass (total dry wt of surviving mussels in a replicate) was generally a more sensitive endpoint compared to survival and growth (length and dry wt). In the 4‐wk NaCl or KCl test started with 2‐mo‐old juveniles, a 20% effect concentration (EC20) based on biomass (264 mg Cl/L from the NaCl test or 8.7 mg K/L from the KCl test) in the exposure with sand was 2‐fold lower than the EC20 in the exposure without sand. The longer‐term 12‐wk NaCl tests started with the 1‐wk‐old and 2‐mo‐old juveniles were successfully completed under refined test conditions based on the feeding study, and younger juveniles were more sensitive to NaCl than older juveniles. The NaCl toxicity did not substantially change with extended exposure periods from 4 to 12 wk, although the 4‐wk EC20s for biomass were slightly greater (up to 37%) than the 12‐wk EC20s in the 2 longer‐term exposures. Including the toxicity data from the present study into existing databases would rank fatmucket the most sensitive species to KCl and the second most sensitive species to NaCl for all freshwater organisms.