High creatinine kinase (CK) levels and leukocytosis are known to be associated with neuroleptic malignant syndrome (NMS). The authors sought to determine if their presence during non-NMS psychotic episodes is predictive of the later development of NMS. Sixteen psychotic inpatients who met the criteria for NMS were included. For statistical comparison, two control groups were formed by matching each study patient with two non-NMS patients for age, gender, ethnicity, and year and ward of hospitalization (n = 32). The maximal individual serum levels of CK, lactate dehydrogenase (LDH), serum glutamic oxaloacetic transaminase (SGOT), and white blood cell count (WBC) during all non-NMS psychotic episodes (Brief Psychiatric Rating Scale 40) were averaged. To normalize the distribution, the individual averages were transformed to natural logarithms (Ln). Mean Ln (average [CK]) in the patients with NMS was found to be 6.46 +/- 0.91 IU/L, and in the non-NMS patients, 5.24 +/- 0.90 IU/L (actual serum CK levels, 911 +/- 747 IU/L and 343 +/- 620 IU/L, respectively). This difference was statistically significant (F [2,15] = 10.5, p < 0.0001). In addition, CK levels above the upper limit of normal were noted in 76% of psychotic episodes in the patients with NMS and in only 30% of psychotic episodes in the non-NMS patients (p < 0.0001). There was no significant difference between the NMS and non-NMS groups in Ln(LDH), Ln(SGOT), or Ln(WBC) (F [2,15] = 1.4, 2.1, and 0.9, respectively). The authors concluded that high serum CK level during non-NMS psychotic episodes seems to be a risk factor for future NMS. Therefore, CK measurement may be justified on admission of acutely psychotic patients who have other risk factors and a history of psychosis-associated CKemia.