Background: This is the first study to compare plasma and cerebrospinal fluid (CSF) pharmacokinetics of intravenous (IV), oral (PO), or rectal (PR) formulations of acetaminophen. Methods: Healthy male subjects (N = 6) were randomized to receive a single dose of IV (OFIRMEV Ò ; Cadence) 1,000 mg (15 minute infusion), PO (2 Tylenol Ò 500 mg caplets; McNeil Consumer Healthcare), or PR acetaminophen (2 Feverall Ò 650 mg suppositories; Actavis) with a 1-day washout period between doses. The 1,300 mg PR concentrations were standardized to 1,000 mg. Acetaminophen plasma and CSF levels were obtained at T0, 0.25, 0.5, 0.75, 1, 2, 3, 4, and 6 hours.Results: IV acetaminophen showed earlier and higher plasma and CSF levels compared with PO or PR administration. CSF bioavailability over 6 hours (AUC 0-6 ) for IV, PO, and PR 1 g was 24.9, 14.2, and 10.3 lgAEh/mL, respectively. No treatment-related adverse events were reported. One subject was replaced because of premature failure of his lumbar spinal catheter. The mean CSF level in the IV group was similar to plasma from 3 to 4 hours and higher from 4 hours on. Absorption phase, variability in plasma, and CSF were greater in PO and PR groups than variability with IV administration.Conclusions: These results demonstrate that earlier and greater CSF penetration occurs as a result of the earlier and higher plasma peak with IV administration compared with PO or PR. n