3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) lyase deficiency, an inborn error of ketone body synthesis and leucine degradation, is a rare autosomal recessive disease. There are a few reports demonstrating clinical and neuroradiologic findings of this condition. The authors report case of an 8-mo-old infant with HMG-CoA lyase deficiency, who presented with macrocephaly, left ventricular noncompaction, recurrent pulmonary infections, nonketotic hypoglycemia, seizure and metabolic acidosis. There was no significant difference in brain magnetic resonance imaging after leucine-restricted diet and carnitine therapy and neurologic deterioration was not observed. Left ventricular noncompaction is an interesting finding for HMG-CoA lyase deficiency which has not been reported in the literature. The genetic analysis revealed a novel homozygote deletion in exon 3 and 4 in HMGCL gene. HMG-CoA lyase deficiency should be thought in the patients with hypoketotic hypoglycemia, hyperammonemia, elevated liver function tests, noncompaction left ventricle and characteristic white matter changes and in the differential diagnosis of macrocephaly.