We describe a child with congenital hypogammaglobulinemia that was diagnosed at 13 months of age. When he was 4 years old, gait disturbances began. The main neurological manifestations were progressive spastic tetraparesis and intellectual and speech deterioration. No infectious agent was identified. A magnetic resonance imaging scan of the central nervous system revealed periventricular demyelinating areas in the frontal, temporal, and parietal lobes with cortical atrophy. Stereotactic brain biopsy confirmed the diagnosis of progressive multifocal leukoencephalopathy caused by JC virus. He was treated with intravenous and intraventricular cytarabine and interferon-alpha, and there was clinical improvement. We emphasize the need for brain biopsy as soon as a neurological complication is suspected in patients with congenital hypogammaglobulinemia for whom cerebrospinal cultures or polymerase chain reaction analyses are negative.