Abstract Background Hypertrophic cardiomyopathy in the neonate has a diverse genetic background, and non-sarcomeric variants may not be identified on commercial genetic testing panels. NDUFB11 is an X-linked mitochondrial Complex I protein and is known to cause histiocytoid cardiomyopathy, but has not been described in female infants with hypertrophic cardiomyopathy. We present this first reported case of obstructive hypertrophic cardiomyopathy in a female neonate secondary to a pathogenic variant in NDUFB11. Case Summary A term female neonate presented following a prenatal diagnosis of biventricular hypertrophy and growth restriction. She developed lactic acidosis after birth and whole genome sequencing identified a de novo variant in the mitochondrial complex I gene, NDUFB11 (c.391G>A, p.Glu131Lys). There was progression of left ventricular hypertrophy and obstruction, with rapid development of heart failure symptoms. She was unresponsive to beta blocker medical therapy and was not suitable for advanced mechanical support. There was subsequent clinical deterioration resulting in death by 3 months of age. Discussion Hemizygous variants in NDUFB11 have been associated with hypertrophic cardiomyopathy in male infants previously, and skewed X-linked inactivation likely resulted in the presentation described here in a female infant. This variant was not identifiable by commercial cardiomyopathy panels. We highlight the importance of rapid whole genome sequencing in cases of infantile hypertrophic cardiomyopathy, and the importance of genetic diagnosis in guiding prognosis and care for these individuals.