Bivalve histopathology is an acknowledged tool in environmental toxicology studies, however geographically restricted, limited to a few species and still lacking the degree of detail needed to develop effective (semi)quantitative approaches. A first-time detailed histopathological screening was performed on grooved carpet shell clams collected from commercial shellfish beds in distinct coastal ecosystems of the Southern Portuguese coast: two parted sites within an impacted estuary (S(1) and S(2)), an inlet channel of a fish farm at a considered pristine estuary (site M) and a site allocated in a clean coastal lagoon (A). A total of thirty histopathological lesions and alterations were analysed in the gills and digestive glands following a weighted condition indices approach, including inflammation-related responses, necrosis, neoplastic diseases and parasites. Digestive glands were consistently more damaged than gills, except for animals collected from site M, where the most severe lesions were found in both organs, immediately followed by S(2). Clams from sites S(1) and A were overall the least damaged. Neoplastic diseases were infrequent in all cases. Inflammation-related traits were some of the most common alterations progressing in animals enduring severe lesions such as digestive tubule (diverticula) and intertubular tissue necrosis. Some alterations, such as lipofuscin aggregates within digestive tubule cells, did not relate to histological lesions. Granulocytomas only occurred in heavily infected tissues. Animals from M and A presented the highest infections in the digestive gland, especially by protozoa. Gill infections were more similar between sites. Still, the level of infection does not account for all histopathological lesions in either organ. Overall, the results are in accordance with environmental parameters, such as distance to pollution sources, sediment type and hydrodynamics, and show that the combination of multiple histopathological features in these clams provides good sensitivity for inter-site distinction even when low or moderate anthropogenic impacts are at stake.