There remains an unmet medical need in the out-of-hospital management of seizure emergencies because older children and adults often refuse treatment with rectal gel due to social objections. We have previously reported that intranasal diazepam (DZP) administration is feasible, with maximum plasma concentrations (Cmax) and time to maximum concentration (Tmax) that are comparable to rectal DZP; but tolerability was poor. In the present study, the tolerability and pharmacokinetics of two investigational nasal formulations were compared with DZP rectal gel. Twelve healthy volunteers were enrolled into an active-control, double-blind, four-period, crossover pharmacokinetic and tolerability study. Three intranasal treatments (Nas-A 10mg, Nas-B 10mg and Nas-B 13.4 mg) were compared to a 10mg dose of the rectal gel. A single dose of each formulation was administered followed by at least a 14 day washout period. Blood samples for plasma DZP concentration-time characterization were collected pre-dose and at regular intervals to 240 h post-dose. Tolerability and sedation were assessed using visual analog scales. Mean DZP Cmax (±SD) was 181.8 ± 84.16, 151.3 ± 108.1 and 180.7 ± 82.1 ng/mL for Nas-A 10mg, Nas-B 10 and Nas-B 13.4 mg respectively; in comparison the Cmax for therectal gel was 160.9 ± 109.4 ng/mL. Median Tmax was 0.75 h for all treatments. Both intranasal formulations were well tolerated and exhibited relatively rapid, but variable, absorption with bioavailability of 70-90% relative to DZP rectal gel. This study shows that the development of a well-tolerated nasal formulation is possible and that the rate and extent of absorption approximates that of DZP rectal gel. We conclude that intranasalDZP offers a viable alternative to rectal administration, but enhancement of formulations is needed to improve the extent and consistency of absorption.