The pro/antioxidant status of marine macrozoobentic organisms is being increasingly applied in environmental monitoring and conservation programs. The oxidative stress level in marine bivalves can provide valuable information not only on the health of the organisms and their populations, but also on the current state of habitats and ecosystems. The aim of the present study was to make the first comprehensive investigation of the seasonal changes in the antioxidant activity in different organs (gills, digestive gland and foot) of M. galloprovincialis from representative Bulgarian Black Sea coastal habitats. The lipid peroxidation and glutathione levels, as well as activities of the antioxidant enzymes catalase, superoxide dismutase, glutathion peroxidase, glutathion reductase, glucose-6-phosphate dehydrogenase and glutathione-S-transferase of the organs were measured spectrophotometrically. Our hypothesis was that enhanced environmental pressure during the summer season, induced by multiple factors (biogenic, abiogenic and anthropogenic) led to weakening of the antioxidant protection in mussels at the beginning of autumn. The reaction of the mussel organism to the multiple stress factors was specific for the target organ and the type of the biomarker. Significant differences were present in the activity of the antioxidant system in mussels from the northern and southern coastal locations. The seasonal changes in the pro/antioxidant status of mussels were primarily due to specific seasonal changes in factors concerning the marine environment at the concrete locality. Further research is obviously needed to confirm the present results and provide a more complete data of seasonal and spatial changes in the antioxidant defense system of mussels from the Bulgarian Black Sea coastal area and their implementation in biomonitoring programs.