Abstract Objective To report a case of neurogenic calf hypertrophy associated with root lesion responsive to botulinum toxin (BTX). In addition, we systematically review the literature for cases of muscle hypertrophy associated with radiculopathy. Methods A 56-year-old man with a previous history of S1 root lesion presented with marked calf hypertrophy, muscle pain, cramps, fasciculations, and increased CK level. Magnetic resonance imaging and muscle biopsy confirmed true muscle hypertrophy. Electromyography (EMG) showed signs of chronic denervation-reinnervation in the right S1 myotome, with greatly increased spontaneous activity (SA) (fasciculations and complex repetitive discharges). Botox® was injected in 3 occasions on 4 sites on the right gastrocnemius (20U per site). Symptoms, CK level and SA on EMG (quantified) were evaluated. Results The patient improved clinically, CK level and SA steadily decreased. Conclusions The lliterature review failed to identify a unique causative factor for muscle hypertrophy related to neurogenic lesions. BTX treatment was effective in our patient with muscle hypertrophy associated with SA. Significance We provide further evidence that spontaneous activity secondary to nerve lesion may cause focal muscle hypertrophy. Treatment with BTX should be considered in these conditions.