Case-control studies have shown that noxious thermal stimulation (TS) can improve arm function in patients with stroke. However, the neural mechanisms underlying this improvement are largely unknown. We explored functional neural activation due to noxious and innocuous TS intervention applied to the paretic arm of patients with stroke. Sixteen participants with unilateral cortical infarctions were allocated to one of two groups: noxious TS (8 patients; temperature combination: hot pain 46°C to 47°C, cold pain 7°C-8°C) or innocuous TS (n = 8; temperature combination: hot 40°C-41°C, cold 20°C-21°C). All subjects underwent fMRI scanning before and after 30 min TS intervention and performed a finger tapping task with the affected hand. Immediate brain activation effects were assessed according to thermal type (noxious vs. innocuous TS) and time (pre-TS vs post-TS). Regions activated by noxious TS relative to innocuous TS (P < .05, adjusted for multiple comparisons) were related to motor performance and sensory function in the bilateral primary somatosensory cortices, anterior cingulate cortex, insula, thalamus, hippocampus and unilateral primary motor cortex, secondary somatosensory cortex at the contralateral side of lesion, and unilateral supplementary motor area at the ipsilateral side of lesion. Greater activation responses were observed in the side contralateral to the lesion, suggesting a significant intervention effect. Our preliminary findings suggest that noxious TS may induce neuroplastic changes unconstrained to the local area.Trial registration: NCT01418404.