PURPOSE: To determine whether the upper cervical cord area (UCCA) is influenced by disease effect in early relapsing-remitting multiple sclerosis (MS), using statistical modeling to account for potential covariates. MATERIALS AND METHODS: A cohort of 39 patients were studied cross-sectionally within three years of first symptom onset (median disease duration = 1.6 years) and compared with 26 healthy controls. The UCCA was measured from axial reconstructions of three-dimensional T1-weighted scans with automated detection of the edge of the cord. Statistical analysis adjusted for factors such as total intracranial volume (TICV) and gender. Clinical correlations, in particular those thought likely to be related to cord pathology, were also investigated. RESULTS: No significant disease effect was noted on UCCA (P = 0.685), although there was borderline evidence of a lower UCCA in patients with symptoms of bowel or bladder disturbance (P = 0.043). A strong association was noted between UCCA and TICV (r = 0.558; P < or = 0.001), and there was a trend for females to have a smaller UCCA (P = 0.062). The latter finding appeared to reflect a gender-related difference in TICV (P < or = 0.001). CONCLUSION: Atrophy of the upper cervical cord is not readily apparent in most patients early in the course of relapsing-remitting MS. In evaluations of disease-related changes in the UCCA in cross-sectional studies, TICV and gender should be considered as potentially confounding covariates.