Among persons with high spinal cord injury (Hi-SCI: > T5), changes in core body temperature (Tcore) and cognitive performance during heat exposure appear related to degree of sympathetic interruption. Twenty men with Hi-SCI (C4-T4, American Spinal Injury Association Impairment Scale [AIS] A-B) and 19 matched, able-bodied controls were acclimated to 27°C baseline (BL) before exposure to 35°C heat challenge (HC). Two groups, differentiated by increase in Tcore during HC, were identified: high responders (HR-SCI: ΔTcore ≥0.5°C; n = 13, C4-T2) and low responders (LR-SCI: ΔTcore <0.5°C; n = 7, C4-T4). Tcore, distal skin temperatures (Tsk(avg)), and distal microvascular perfusion (LDF(both feet)) were measured, as were indices of sympathetic integrity, mean arterial pressure (MAP), and extremity sweat rate (SR(avg)). Cognitive performance was assessed at BL and post-HC, using the Stroop Color and Word and Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) Digit Span tests. At BL, Tcore of the HR-SCI group (36.6 ± 0.4°C) was lower than that for the LR-SCI (37.1 ± 0.3°C; p = 0.011) and control groups (37.3 ± 0.3°C; p < 0.001). After HC, Tcore was not different among groups. MAP of the HR-SCI group (70.9 ± 9.8 mm Hg) was lower than that of the LR-SCI (81.8 ± 7.0 mm Hg; p = 0.048) and control groups (89.9 ± 9.9 mm Hg; p < 0.001). SR(avg) increased more in the control group (77.0 ± 52.5 nL/cm(2)/min) than in the HR-SCI group (15.5 ± 22.0 nL/cm(2)/min; p = 0.001). Only the HR-SCI group had significant increases in T-Scores of Stroop Word (7.5 ± 4.4; p < 0.001), WAIS-IV Digit Span Sequence (1.9 ± 1.8; p = 0.002), and WAIS-IV Digit Span Total (1.4 ± 1.6; p = 0.008). Persons with SCI who responded to HC with a greater change in Tcore demonstrated evidence of greater sympathetic interruption and had an associated improvement in cognitive performance.