Background: We set out to test the discriminative power of an age-adjusted upper reference limit (URL) for CSF total protein (CSF-TP) in identifying pathological causes of albuminocytologic dissociation (ACD). Methods: We reviewed the charts of 2,627 adult patients who underwent a lumbar puncture at a tertiary care center over a 20-year period. Samples with CSF-TP above 45 mg/dL (0.45 g/L) were included. Samples with white blood cell count > 5×109/L, red blood cell count > 50×109/L, and glucose < 2.5 mmol/L (45 mg/dL) were excluded. Patients with CSF-TP elevated above 45 mg/dL were considered to have ‘pseudo’ albuminocytologic dissociation (ACD) or ‘true’ ACD if their CSF-TP was in excess of age-adjusted norms. Results: Among all patients with ACD, a pathological source of CSF-TP elevation was identified in 57% (1490/2627) of cases, 51% of those with ‘pseudo’ ACD, and 75% with ‘true’ ACD (p< 0.001). Use of an age-adjusted upper reference limit favored the detection of polyneuropathy patients (13.5% proportionate increase) and excluded a larger number of patients with isolated headache (10.7% proportionate decrease; p < 0.0001). Conclusions: Elevated CSF-TP is a relatively common finding. Use of age-adjusted upper reference limits for CSF-TP values improve diagnostic specificity and help to avoid over-diagnosis of ACD.