ABSTRACT: Lysosomal responses in mussel digestive cells are widely accepted as effective biomarkers that respond to pollutant exposure, as well as to natural factors (tide, food, temperature). The effects of tide and season on digestive cell lysosomes in mussels were determined in different transect and transplant experiments on mussels at different tide levels and in winter and summer. We measured lysosomal enlargement through the lysosomal structural changes (LSC) test after β-glucuronidase (β-Gus) histochemistry and membrane destabilisation through the lysosomal membrane stability (LMS) test after hexosaminidase (Hex) histochemistry. A marked gradient along the intertidal zone, which was more prominent in winter than in summer, was found in lysosomal size and membrane stability. A transplant experiment revealed that digestive cell lysosomes respond rapidly to immersion of mussels. The study of the time-course changes in mussels from high tidemark level indicated that lysosomes respond very promptly to air exposure conditions. We suggest that the lysosomal changes observed are the result of the digestive process in parallel with tide. Since such natural variability might mask the effects of pollution, we conclude that a standardised sampling protocol—which should include the use of mussels from low intertidal levels—is needed.