To better understand the mechanisms that lead to marine mortality of homing adult sockeye salmon (Oncorhynchus nerka), gill and blood biopsies were used in combination with biotelemetry to demonstrate how survival to freshwater entry is related to gene expression and physiological indices of stress. Microarray analysis of gene expression indicated multiple biological processes, including immune and stress responses, protein biosynthesis, and metabolism. Quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) analysis indicated fish with upregulation of genes related to stress and infection had higher marine survival compared with fish without this genomic signature. We proposed that higher marine survival of potentially stressed and immune compromised fish can be explained by stressed and infected fish being highly motivated to enter fresh water, leading to enhanced marine survival. However, once in a river, stressed and immune compromised fish could suffer higher mortality because of premature river entry. Overall, this study supports the idea that infection and stress are important biological processes influencing behaviour and fate of sockeye salmon during homing migrations.