Loxapine substitution is a promising option for patients with autism spectrum disorder (ASD) who develop antipsychotic-induced metabolic illness. We performed a chart review of 15 adolescents and adults meeting DSM-IV-TR criteria for ASD, all with antipsychotic-associated weight gain, who received low dose loxapine in an attempt to taper or discontinue the weight gain-associated antipsychotic. Mean weight loss was -5.7 kg, mean BMI reduction was -1.9, and mean triglyceride reduction was -33.7 mg/dl. At chart review, 14 of 15 subjects were rated 2 (Much Improved) or 1 (Very Much Improved) on the Clinical Global Impressions-Improvement scale (CGI-I). Low dose loxapine addition in most cases enabled taper of offending antipsychotics, significantly reversed drug-induced metabolic disturbances and improved irritability.