Measured maximal oxygen uptake (VO 2peak ) is the gold standard to assess exercise tolerance functions. However, this measure can be very challenging in patients suffering from multiple sclerosis (MS) because of several limiting factors (e.g., fatigue, pain, unfamiliarity with exercise, lack of mobility…). Various submaximal indices have been studied to assess exercise tolerance functions in healthy subjects and in persons with neurological conditions. However, whether they relate to the gold standard have been barely studied. Our aim was to explore the relations between simplified exercise indices and VO 2peak among patients with MS and healthy controls. This case-control study included 39 patients with MS (mean age: 45 ± 10 years; median EDSS 2.5 (range 0–4)) and 30 healthy subjects (HS) (mean age: 44 ± 8 years). Participants performed a stepwise maximal exercise testing on a cycle ergometer. VO 2peak , oxygen uptake efficiency slope (OUES) derived from different reference periods of the exercise test. Descriptive statistics, Student's T -tests, Pearson's correlation coefficients between VO 2peak and simplified indices and Fisher Z -tests were computed. Measured VO 2peak was also compared to PeakWR-based estimation of VO 2max by the Bland-Altman method. VO 2peak and all the simplified indices were significantly lower in the MS group compared to the HC group ( P < 0.001). OUES appeared highly correlated (> 0.70, P < 0.001) with VO 2peak , in both groups, without difference between groups. The relation slightly, but not significantly, increased with the duration period of the test taken into account of the exercise, in both groups. PeakWR-based prediction of VO 2peak presented a standard error of the estimate of 315 ml/min (10.7%) in HS, and 176 ml/min (12.5%) in MS. HR-based index appeared lowly-to-moderately correlated to VO 2peak in both groups. OUES seem to be valid when comparing with gold standard, in both group, even for short-lasting submaximal efforts. PWR-based equation predicts VO 2peak with an accuracy of 10%, at a group level.