One of the distinguishing features of the ventral premotor cortex (area F5) is that low-threshold repetitive intracortical microstimulation (rICMS) evokes digit movements. We investigated whether these motor effects result from a direct influence upon the spinal networks controlling digit movements or upon cortico-cortical connections with the primary motor cortex (M1). We evoked digit movements from F5 or M1 using small arrays of low impedance chronically implanted microwires and then tested whether these motor responses were affected by local microinjections of the GABA_A agonist muscimol into the hand area of M1. Two macaque monkeys were used. The hand area in both F5 and M1 were first localised using structural MRI and subsequent mapping of both areas using rICMS at low threshold (< 10 ¼A in M1 and < 20 ¼A in F5). During mapping, monkeys were lightly sedated using ketamine/medetomidine (6.4 mg kg^-1/80 ¼g kg^-1, respectively). After mapping was complete, chronic microwires were implanted under deep anesthesia (intubation with isoflurane at 2-2.5% in a 1:1 O₂-N₂O mixture) at the centres of the hand/digit representations of M1 and F5. The length, arrangement and implantation angle of each array was based upon the ICMS mapping results, and targeted the rostral bank of the central sulcus (M1) and inferior limb of the arcuate sulcus (F5). Each 5-electrode array carried a guide tube that could carry the needle of a microsyringe for muscimol delivery. After implantation, rICMS was delivered to arrays so as to evoke stable EMG responses recorded from digit muscles. The effects of rICMS delivered to F5 while M1 was inactivated were investigated. Within 10-20 min after microinjection of muscimol (0.5%, 1.5 ¼l) in the M1 hand area, there was a dramatic decrease in the evoked digit muscle EMG activity evoked from F5. Behavioural deficits restricted to the hand contralateral to the injection site were observed during the recovery period immediately after recovery from sedation. Control injections of saline in M1 were without effect. In a further control experiment, we noted that EMG responses to direct stimulation of the medullary pyramid were only slightly decreased after M1 muscimol inactivation, arguing against a decrease in spinal or motoneuronal excitability as the explication of the loss of F5-evoked activity. In conclusion, the results argue against a direct influence of F5 on hand motoneurones via the corticospinal tract, but rather suggest that M1 plays a key role in the transmission of output from F5 to hand motoneurones.