The aim of the present study was to establish the changes in nerve excitability and symptom generation associated with the application of focal nerve compression (FNC). FNC was applied at the wrist by means of a custom-designed electrode in 10 healthy subjects, and was maintained for 24 min. Symptoms of paraesthesiae and signs of numbness were recorded every 30 s. Despite apparently minimal changes in axonal threshold, FNC was associated with prolongation in latency by 14.5 +/- 2.1% (P < 0.001) and reduction in compound sensory action potential (CSAP) amplitude by 34.3 +/- 5.1% (P < 0.001), with two subjects developing conduction block. The reduction in CSAP was associated with abolition of superexcitability, and an increase in refractoriness of 295.2 +/- 55.5% (P < 0.005) and strength-duration time constant (SDTC) by 48.1 +/- 10.3% (P < 0.005), all consistent with axonal depolarization. With release of FNC, threshold rapidly increased above pre-compression levels (P < 0.01), consistent with the development of axonal hyperpolarization. Associated with these changes in axonal excitability, paraesthesiae and numbness steadily increased throughout FNC and reached a peak at the termination of FNC, followed by a gradual recovery on release of FNC. When compared to previous studies that utilised the effects of more generalised limb ischaemia, the changes in axonal excitability recorded during FNC were qualitatively and quantitatively alike, suggesting that similar biophysical mechanisms contributed to the changes observed with both manoeuvres.