PURPOSE Gait deviations are common in patients with multiple sclerosis (MS) and can increase the risk of falls and potential for musculoskeletal pain. This study evaluated relationships between fatigue-induced changes in lower extremity kinematics and spatiotemporal measures during a Six-Minute Walk Test (6MWT). METHODS Baseline data from 29 participants ((age 49±12 years, 21F, Expanded Disability Status Scale 1-5.0) with MS completed the 6MWT. Gait parameters were recorded continuously via inertial measurement units (Xsens MVN, Enschede, Netherlands). Peak joint angles (knee flexion, hip adduction, trunk angular displacement) and spatiotemporal measures (gait speed, stance time, stride length) were calculated and analyzed for each walking stride during the first and last minute of the test. Pearson correlations were used to evaluate 1) relationships between the Distance Walked Index (DWI, difference in distance between first and last minute) and changes in involved (i) and uninvolved (u) limb peak joint angles and 2) relationships between changes in gait parameters, spatiotemporal measures, and 6MWT DWI. Paired t-tests evaluated differences in peak joint angles between the first and last minute of the 6MWT. RESULTS Participants demonstrated a 7.0% decline on the DWI (4.3 ± 6.4m reduction in walking distance) and gait speed declined by 8.5% (0.07 ± 0.11 m/s) between the first and last minute of the 6MWT. A weak, negative correlation was observed between change in frontal trunk angular displacement and DWI (R= -.501, p= .009). There were no changes in stance timei or stance timeu. Stride length decreased on both limbs over time (Mean Difference (MD)i: 3.2cm, p <.001; MDu: 3.2cm, p<.001). Within-limb peak knee flexion angle decreased on both limbs over time (MDi: -6.7±14.1°, p=.021; MDu: -8.11±14.7°, p=.008). CONCLUSION Gait deviations presented as decreased stride length and bilateral reduced peak knee flexion angle during the 6MWT. Greater DWI was associated with reduced trunk angular displacement. Interventions targeting hip and knee joint-specific dysfunction may be advantageous for mitigating gait deviations in patients with MS. Gait deviations are common in patients with multiple sclerosis (MS) and can increase the risk of falls and potential for musculoskeletal pain. This study evaluated relationships between fatigue-induced changes in lower extremity kinematics and spatiotemporal measures during a Six-Minute Walk Test (6MWT). Baseline data from 29 participants ((age 49±12 years, 21F, Expanded Disability Status Scale 1-5.0) with MS completed the 6MWT. Gait parameters were recorded continuously via inertial measurement units (Xsens MVN, Enschede, Netherlands). Peak joint angles (knee flexion, hip adduction, trunk angular displacement) and spatiotemporal measures (gait speed, stance time, stride length) were calculated and analyzed for each walking stride during the first and last minute of the test. Pearson correlations were used to evaluate 1) relationships between the Distance Walked Index (DWI, difference in distance between first and last minute) and changes in involved (i) and uninvolved (u) limb peak joint angles and 2) relationships between changes in gait parameters, spatiotemporal measures, and 6MWT DWI. Paired t-tests evaluated differences in peak joint angles between the first and last minute of the 6MWT. Participants demonstrated a 7.0% decline on the DWI (4.3 ± 6.4m reduction in walking distance) and gait speed declined by 8.5% (0.07 ± 0.11 m/s) between the first and last minute of the 6MWT. A weak, negative correlation was observed between change in frontal trunk angular displacement and DWI (R= -.501, p= .009). There were no changes in stance timei or stance timeu. Stride length decreased on both limbs over time (Mean Difference (MD)i: 3.2cm, p <.001; MDu: 3.2cm, p<.001). Within-limb peak knee flexion angle decreased on both limbs over time (MDi: -6.7±14.1°, p=.021; MDu: -8.11±14.7°, p=.008). Gait deviations presented as decreased stride length and bilateral reduced peak knee flexion angle during the 6MWT. Greater DWI was associated with reduced trunk angular displacement. Interventions targeting hip and knee joint-specific dysfunction may be advantageous for mitigating gait deviations in patients with MS.