Dysregulation of glutamate neurotransmission plays a critical role in autism spectrum disorder (ASD) pathophysiology and is a primary target for core deficit research treatment trials. The mechanism of action of ketamine has striking overlap with the theory of ASD as a disorder of synaptic communication and neuronal networks. This two-dose, double-blind, placebo controlled, cross-over pilot trial of intranasal (IN) ketamine targeting core social impairment included individuals with ASD (N = 21) between 14 and 29 years. Participants were randomized to received two doses of IN ketamine (30 and 50 mg) and two doses of matching placebo. No significant impact was noted on the Aberrant Behavior Checklist Social Withdraw subscale. The IN ketamine was well tolerated, with only transient mild adverse effects.