The effects of seizures on the hypocretin/orexin system have not yet been investigated in epileptic patients. The present study aimed to assay hypocretin-1 in the cerebrospinal fluid (CSF) of patients after generalized tonic-clonic (GTC) seizures. Study groups consisted of 21 patients after GTC seizures and 19 controls. Diagnostic lumbar puncture was performed in control and epileptic patients within 48 h after the GTC seizures. Hypocretin-1 levels were measured in unextracted CSF samples, using a standardized commercial radioimmunoassay. There was a significant overall difference in median CSF hypocretin-1 concentrations between controls and patients with GTC patients (p < 0.001). The lowest concentrations were noted in a subgroup of patients with repetitive GTC seizures (RS) compared to those with a single GTC seizure (SS) (p > 0.05) or controls (p < 0.001). The current results suggest that the hypocretin-1 system deficiency contributes to the complex pathophysiology of repetitive GTC seizures and status epilepticus (SE) and could be associated with typical somnolence after seizure attacks.