ABSTRACT: A single dose (40 mg kg^–1) of erythromycin or azithromycin dihydrate was injected intraperitoneally into maturing female fall Chinook salmon 12 to 32 d before spawning to observe the distribution, retention and clearance of the drugs in plasma, kidney, coelomic fluid and egg vitellin, and their persistence in alevins derived from these fish. Salmon administered prophylactic dosages of erythromycin as subadults were also included to investigate potential interactive effects of oral and injected treatments on reproductive performance and antibiotic clearance. Erythromycin was rapidly cleared from plasma and coelomic fluid, but was detected in the kidney (3.52 to 12.40 µg g^–1) and egg vitellin (5.32 to 8.87 µg ml^–1) of all fish at spawning. High, stable concentrations of azithromycin were detected in plasma (14.66 to 20.33 µg ml^–1), kidney (43.16 to 59.96 µg g^–1), coelomic fluid (2.52 to 5.50 µg ml^–1) and egg vitellin (12.65 to 23.51 µg ml^–1). Oral administration of erythromycin to subadult salmon did not significantly affect tissue concentrations of either erythromycin or azithromycin administered by prespawning injection. Reductions in the percentage of eggs that yielded live embryos at the eyed stage of development occurred among eggs derived from females that had received orally administered erythromycin as subadults. Erythromycin was not detected in unfed fry derived from adults injected with the drug prespawning, but azithromycin was present for more than 2 mo after the onset of exogenous feeding.