While adaptations to a short-term training program can dampen the acute inflammatory response to exercise, less is known about the influence of chronic modality-specific adaptations to training. This study compares the acute inflammatory response to upper- and lower-body interval exercise in individuals chronically trained in these respective modalities. Ninety minutes of interval exercise matched for relative power output on an arm-crank (ARM) and cycle ergometer (LEG) was performed by 8 trained paddlers and 8 trained cyclists. Blood samples were taken before and after exercise. Interleukin-6 (IL-6) concentrations were analysed in plasma, while the expression of intracellular heat shock protein 72 (iHsp72) was assessed in monocytes. IL-6 was increased following both modalities (fold change – ARM: 7.23 ± 3.56, p < 0.001; LEG: 9.03 ± 4.82, p < 0.001), in both groups (cyclists, p < 0.001; paddlers, p < 0.001), but the increase was smaller in ARM compared with LEG (time × modality, p < 0.001). ARM induced a smaller iHsp72 response compared with LEG (fold change – ARM: 1.07 ± 0.14, p = 0.102; LEG: 1.18 ± 0.14, p < 0.001; time × modality, p = 0.039). Following ARM, iHsp72 expression was increased in the cyclists only (fold change cyclists: 1.12 ± 0.11, p = 0.018; paddlers: 1.03 ± 0.17, p = 0.647), while iHsp72 expression following LEG was increased in both groups (fold change cyclists: 1.14 ± 0.15, p = 0.027; paddlers: 1.22 ± 0.13, p < 0.001). Taken together, the acute inflammatory response to lower-body interval exercise was larger compared with work-matched upper-body interval exercise. Moreover, adaptations to upper-body exercise training dampened the iHsp72 response to this modality. Therefore, exercise may be less effective in reducing chronic low-grade inflammation in individuals relying on their upper body, such as wheelchair users.