The course of the palmar cutaneous branch of the median nerve (PCBMN) was studied in 25 fresh cadaveric upper extremities in order to identify its relation to local structures and commonly used incisions for carpal tunnel release. The PCBMN was found to closely underlie the thenar crease (average, 0-2 mm radial to crease; range, 6 mm ulnar to 6 mm radial to thenar crease), suggesting that an incision fashioned in the thenar crease would lead to frequent PCBMN injury. The PCBMN was also found to cross the axis of the ring finger when the axis was determined with the finger flexed into the palm. The axis of the ring finger, as drawn with the ring finger extended, projected in a more ulnar direction. The PCBMN was an average of 9 mm radial to this projection (range, 1-16 mm). An analysis of 100 human volunteer hands demonstrated that the deepest point between the thenar and hypothenar eminencies was a constant landmark in the proximal palm (interthenar depression). The PCBMN traveled an average of 5 mm radial to the interthenar depression (range, 0-12 mm radial). Thenar crease anatomy and ring finger projection were highly variable both in absolute location and configuration, providing a poor basis for incision placement. An incision placed approximately 5 mm ulnar to the interthenar depression, extending in the direction of the third web space, will decrease the incidence of injury to the PCBMN.