Objective: To study the clinical and pathological correlations of neuromuscular patients with a high aldolase and normal creatine kinase (CK) in serum at presentation or during a symptomatic exacerbation. Methods: Records and muscle biopsies were retrospectively reviewed in a consecutive series of 12 patients. Pathological results were compared to 75 abnormal muscle biopsies associated with acquired immune or inflammatory myopathy syndromes and 14 muscle biopsies from patients with myopathies associated with serum anti-Jo-1 antibodies. Results: All patients with selectively elevated serum aldolase had muscle discomfort (92%), weakness (proximal and distal) (50%), or both. Frequent systemic features included joint pain (75%), skin disorders (75%) and pulmonary involvement (50%). Electromyography patterns included normal (36%), non-irritable myopathy (45%) and irritable myopathy (18%). Jo-1 antibodies were not found in the five patients tested. The distinctive feature of muscle biopsies was perimysial pathology (92%), including acid phosphatase positive cellularity (83%) and fragmented connective tissue (75%). Conclusions: Selectively elevated serum aldolase is associated with syndromes including myopathies with discomfort and weakness, systemic disorders and myopathology in perimysial connective tissue. The myopathy with perimysial pathology and the associated clinical syndromes seen in our patients are similar to disorders associated with antisynthetase antibodies. In patients with muscle discomfort or mild weakness and a normal CK, measurement of serum aldolase can be useful in the evaluation of possible myopathies.