The aim of this review was to evaluate the sensitivity and specificity of postictal creatine kinase (CK) levels in the differential diagnosis of epileptic seizures (ES) and psychogenic non-epileptic seizures (PNES). A systematic search was conducted for studies that evaluated postictal CK levels in patients with ES (all types) and PNES. Sensitivity and specificity with 95 % confidence intervals were determined for each study, taking into account: (a) the upper limits adopted; and (b) the 95.7th percentile values, which are recently proposed practical upper reference limits for CK activity. Four studies, comprising a total of 343 events (248 ES and 95 PNES), were available for analysis. Most patients (47/78, 60 %) with ES considered had primarily or secondarily generalized tonic-clonic seizures. The sensitivity of increased postictal CK levels for ES ranged from 14.6 to 87.5, whereas specificity ranged from 85.0 to 100.0. At the 95.7th percentile threshold, sensitivity ranged from 14.6 to 62.5 and specificity was 100.0. The limited number of studies available, their small sample size, and lack of individual event data prevented further stratification analysis by seizure type. Despite the clinical heterogeneity and the limitations of the included studies, increased postictal CK levels are highly specific for the diagnosis of ES, although no definite conclusion on its role in differentiating between convulsive and non-convulsive ES can be drawn. Postictal serum CK levels can provide valuable retrospective information at the later stages of the differential diagnosis of ES and PNES. Due to low sensitivity, normal postictal CK levels do not exclude ES.