Episodic memory impairment is a well-recognized feature of mesial temporal lobe epilepsy. Semantic memory has received much less attention in this patient population. In this study, semantic memory aspects (word–picture matching, word definition, confrontation and responsive naming, and word list generation) in 19 patients with left and right temporal lobe epilepsy secondary to mesial temporal sclerosis (MTS) were compared with those of normal controls. Patients with LMTS showed impaired performance in word definition (compared to controls and RMTS) and in responsive naming (compared to controls). RMTS and LMTS patients performed worse than controls in word-picture matching. Both patients with left and right mesial temporal lobe epilepsy performed worse than controls in word list generation and in confrontation naming tests. Attentional-executive dysfunction may have contributed to these deficits. We conclude that patients with left and right MTS display impaired aspects of semantic knowledge. A better understanding of semantic processing difficulties in these patients will provide better insight into the difficulties with activities of daily living in this patient population.