Enzyme elevations are frequently observed in neuroleptic malignant syndrome (NMS), but their significance is unknown and their source is uncertain. In this study the relationship of serum enzymes to creatine phosphokinase (CPK) in NMS is examined. Thirty-seven patients with at least one probable episode of NMS were studied, and 83 consecutive newly admitted psychiatric patients constituted a comparison group. Serum levels of lactate dehydrogenase (LDH), glutamic oxaloacetic transaminase (GOT), aldolase, and alkaline phosphatase (AP) were compared to serum CPK levels in each patient group. Except for AP, all enzymes were significantly correlated with CPK in both groups. However, correlations were much higher in the NMS group, and regression lines for CPK-LDH and CPK-GOT pairs differed significantly between patient groups. These data strongly suggest that a common process underlies the enzyme elevations frequently seen in NMS, that these enzymes originate in muscle tissue, and that these findings are not caused solely by agitation or psychological stress. It is likely that increased production and selective ''leakage'' of enzymes from myocytes play a role in this process.