Reproductive-based migration is a challenging period for many animals, but particularly for Pacific salmonids, which must navigate from the high seas to freshwater natal streams. For the first time, we attempt to answer the question as to why some migratory adult Pacific salmon die en route to spawning grounds. Summer-run sockeye salmon (Oncorhynchus nerka) were used as a model, and the migration behavior of 301 fish was followed by intercepting them in the ocean about 215 km from the mouth of the Fraser River, British Columbia, Canada, and implanting a gastric radio transmitter. Before release, telemetered fish were also bio-sampled, which included drawing a blood sample, collecting a gill biopsy, and quantifying energetic status with a microwave energy meter. We tested the predictions that the fish that died prematurely would be characterized by low energy reserves, advanced reproductive development, elevated indicators of stress, and low osmoregulatory preparedness compared with fish that completed their river migration. Just over half (52.3%) of the sockeye tagged were subsequently detected in the Fraser River. Salmon that failed to enter the river had exhibited indicators of stress (e.g., elevated plasma lactate, glucose, and cortisol). Contrary to our prediction, fish that failed to enter the river tended to have higher gross somatic energy and be larger at the time of sampling in the ocean than fish that successfully entered the river. Of the fish that were detected in the river (i.e., 134 fish excluding fishery removals), 9.7% did not migrate beyond the lower reaches (approximately 250 km from ocean), and a further 14.2% reached the upper reaches but failed to reach natal sub-watersheds, whereas the remainder (76.1%) reached natal sub-watersheds. Of these, fish unsuccessful in the lower reaches tended to have a high plasma osmolality in the ocean, whereas fish failing in the upper reaches had lower levels of reproductive hormones in the ocean.