The edible mussel Lithophaga lithophaga is considered as one of the most important human food sources in Alexandria, Mediterranean Sea. The present study is designed to determine the seasonal bioaccumulation levels of Cd, Co and Pb in the whole soft tissues as well as different tissues of Lithophaga lithophaga. Results revealed that the seasonal bioaccumulation levels of Cd, Co and Pb in date mussel were below the permissible limits or other reported values from other regions of the Mediterranean. On the other hand, the order of metals accumulation level in different tissues was as follows: digestive gland>remaining soft tissues>gonads. The present study confirmed the role of digestive gland as a concentration center for heavy metals. Moreover, total protein content and stress protein responses of the whole soft tissues were evaluated. The total protein content was arranged in the following order: summer>autumn>spring>winter. Five novel stress proteins appeared in summer. The histological and ultrastructural studies of the digestive gland of Lithophaga lithophaga collected in summer and spring showed marked histopathological alternations.