Epilepsy is a common neurological disorder in veterinary practice, complicated by frequent occurrence of medication-resistant epilepsy. In human medicine, it has been noted that some patients with medication-resistant epilepsy have in fact other reasons for their apparent medication-resistance. The aim of this retrospective study was to describe the issue of pseudoresistance using as an example a population of dogs presented with presumed medication-resistant epilepsy and provide an in-depth review of what is known in human medicine about pseudoresistant epilepsy. One-hundred fifty-two cases were identified with medication-resistant epilepsy, of which 73% had true medication-resistant epilepsy and 27% patients had pseudoresistance. Low serum anti-seizure medication levels were the most common cause of pseudoresistance, present in almost half of the cases (42%), followed by inadequate choice of drugs or dosages (22%), misclassification (22%) or misdiagnosis (9%) of epilepsy and poor compliance (9%). All cases of pseudoresistance, except for one, responded to a modification of the initial therapy protocol. Pseudoresistance can bias clinical trials, misinform the clinical decision-making process, delay diagnosis and treatment, and misinform owners about their pets’ prognosis. A substantial proportion of these cases can have improvement of their seizure frequency or achieve seizure freedom upon modification of their therapeutic protocol.