Three genetic loci for the Charcot-Marie-Tooth (CMT) syndromes with slow motor nerve conduction velocities (hereditary motor and sensory neuropathy: HMSN type I) have been mapped to chromosomes 1 (CMT1B), 17 (CMT1A), and the X chromosome (CMTX). The clinical features of these three CMT subgroups are similar. To determine whether any clinical features distinguish CMTX families, the range of clinical findings and motor nerve conduction velocities were examined in two large CMTX families with CMTX proven by linkage to X-chromosome markers. CMTX males had more wasting and weakness than CMTX females or individuals with CMT1A. Patellar reflexes were more often retained in CMTX. Motor nerve conduction velocities were faster than in CMT1A. Intermediate-range median nerve conduction velocities were present in CMTX females (45 ± 9 m/sec; range, 26 to 61 m/sec). These velocities were significantly faster than those for CMT1A females (22 ± 8 m/sec, p < 0.0001). Median nerve conduction velocities in CMTX males (31 ± 6 m/sec) were significantly slower than in CMTX females and faster than in CMT1A males (20 ± 6 m/sec, p < 0.0001). The combination of slow conduction velocities in affected males (<40 m/sec) and intermediate-range median motor conduction velocity results (>40 m/sec) in affected or obligate carrier females is a useful distinguishing feature to separate CMTX from CMT1A, as intermediate conduction velocities are not present in autosomal-dominant CMT1A families. This feature defines possible CMTX families for linkage studies. Families with no male-to-male inheritance of the syndrome, slow motor nerve conductions in affected males, and normal or intermediate-range conduction velocities in carrier females should be considered to be X-linked CMT families.