OBJECTIVES: This study aimed to investigate whether neurological disability status, heart rate variability (HRV), cardiorespiratory fitness (CRF) explained the variance in depressive symptoms in multiple sclerosis (MS). METHODS: Associations between CRF (via maximal oxygen uptake; VO(2peak) ), HRV indices of normalized ultra-low (nULF) and very low frequency domains (nVLF), neurological disability status and depressive symptoms (using the Depression subscale of the Hospital Anxiety Depression Scale; HADS-D) were assessed in 53 participants with MS and 17 matched controls. Hierarchical linear regression analysis was conducted within the MS subsample to examine the variance explained by neurological disability alone and CRF. RESULTS: The groups were similar in mean age (MS=52.0 years, Control=51.1 years) and sex (MS=72% female, Control=77% female). Among individuals with MS, HADS-D scores significantly correlated with disability status (sample mean score=4) and VO(2peak) (r=-.62, P<.001), whereas VO(2peak) only correlated with nVLF (r=0.29, P<.05), but not nULF (r=0.26, P=.06). The hierarchical linear regression indicated that VO(2peak) (P<.05) attenuated the effect of disability status on HADS-D scores such that disability was no longer a predictor of depressive symptomology at step 2 (P>.05). CONCLUSION: Heart rate variability does not seem to significantly differ between individuals with MS and healthy controls. When accounting for CRF, disability status no longer explains significant variance in depressive symptoms in MS. Accordingly, targeting CRF might be an effective approach for effectively managing depressive symptoms in individuals with MS.