Mussels are an ecologically and economically important taxon that attach to solid surfaces via the byssus. To date, little is known about the effects of ocean acidification (OA) on mussel byssal attachment and the underlying molecular byssal responses. This study demonstrated that after 1 week of exposure to acidified seawater, both mechanical properties and the number of byssal threads produced by Mytilus coruscus were significantly reduced, leading to a 60 to 65% decrease in mussel byssal attachment strength. Real-time PCR results suggested that OA also altered the expression of genes encoding the proximal thread matrix protein, precursor collagen proteins and mussel foot proteins. OA may weaken mussel byssal attachment by reducing the production and mechanical properties of byssal threads and by inducing byssal molecular responses. The weakened byssal attachment induced by OA therefore could pose a substantial threat to both mussel aquaculture and mussel-bed ecosystems.