Numerous patients who are prescribed antiepileptic drugs (AEDs) for epileptic seizures are already receiving other agents for the treatment of co-morbid conditions, which frequently occur alongside epilepsy. This raises additional clinical considerations and makes the use of AEDs with good safety profiles and fewer drug–drug interactions attractive. Second and third-generation anticonvulsant drugs are associated with fewer pharmacological interactions and improved tolerability compared with first-generation drugs. Furthermore, second and third-generation anticonvulsant drugs are associated with linear pharmacokinetic profiles and differing mechanisms of action, making them ideal for pluripathological and polymedicated patients. In this report, we highlight the efficacy of one such agent, lacosamide, in five patients with co-morbidities and unusual presentations of epilepsy, including a patient with paraneoplastic encephalitis caused by microcytic lung carcinoma, one with a brain tumour and one with Alzheimer's disease, as well as a case of catamenial epilepsy and one of refractory convulsive status epilepticus. In all patients, lacosamide was associated with a substantial reduction in seizure frequency and effective control of seizure episodes. Treatment was generally well tolerated in all patients, indicating that lacosamide is an effective treatment option for a variety of patients with epileptic seizures.