From 8322 patients for whom creatine kinase (CK; EC 2.7.3.2) isoenzyme analysis was ordered, we identified 136 patients with macro CK isoenzyme in their serum. There were 36 cases with type 1 (prevalence: 0.43%) and 100 cases with type 2 isoenzyme (prevalence: 1.20%). About three-fourths of the patients were ambulatory at the time of testing, and approximately 90% of the first 68 patients identified survived at least 1 year after macro CK was found in their serum. Age and gender did not differ significantly between the two groups. The serum total CK was significantly higher (P < 0.0005), and an increased CK-MB proportion (> 0.05 of total CK) was also significantly more common (P < 0.0005) in patients with macro CK type 1 than in those with type 2. On average, macro CK type 2 accounted for approximately 25% and macro CK type 1 for approximately 10% of the serum total CK activity. Patients with macro CK type 1 most often had myositis, whereas those with macro CK type 2 most commonly had a malignancy. We conclude that the presence of macro CK isoenzymes has a low prognostic value for impending death, but may support the diagnosis of an autoimmune process (type 1) or malignant cell proliferation (type 2).