The Manila clam (Ruditapes philippinarum) is an important economic resource for fisheries in the Lagoon of Venice, where this species is fished and farmed. With the aim of evaluating possible fishing-induced long-term effects undergone by clam populations subjected to fishing efforts, physiological biomarkers were measured at organism level (clearance and respiration rates, scope for growth and survival-in-air test). Clams were collected on a seasonal basis from sites characterized by various fishing management practices: a free fishing area at S. Angelo and an area licensed for clam farming at Chioggia, where a non-fishing sub-area was established. R. philippinarum collected at S. Angelo generally showed reduced filtering activity and higher oxygen consumption, revealing general worsening in clam well-being in comparison with individuals from both Chioggia areas. This condition, resulting in lower standardized scope for growth values, may be explained by both environmental and fishing effort differences. Comparing Chioggia samples, better physiological performances were exhibited by clams from the non-fishing area, though no significant differences were observed. In winter, the survival-in-air test revealed the detrimental effects of fishing on clams, whereas in the other seasons this response generally seemed to be mostly related to other exogenous and endogenous factors. Although differences among sites and seasons were always statistically significant, all physiological parameters indicate the great tolerance of R. philippinarum to changing environmental conditions.Ruditapes philippinarum, Lagoon of Venice, physiological responses, scope for growth, fishing impact, clam culture.