This study sought to compare the respective effects of resistance or aerobic exercise of higher or lower intensities on the acute plasma interleukin-6 (IL-6) and C-reactive protein (CRP) response in a sedentary, middle-aged, disease-free cohort. Following baseline testing, and in a randomized cross-over design, 12 sedentary males completed four exercise protocols, including 40 min of moderate-vigorous (M-VA) or low-intensity (LA) aerobic exercise on a cycle ergometer; and a moderate-vigorous (M-VR) or low-intensity (LR) full-body resistance session matched for protocol duration. Venous blood was obtained pre-, post-, 3 h post and 24 h post-exercise and analysed for IL-6, CRP, leukocyte count, myoglobin, creatine kinase (CK), and cortisol. Diet and physical activity were standardized 24 h before and after exercise. Results indicated an elevated CRP response in the M-VR protocol in comparison to the low-intensity protocols (P < 0.05); however, no changes were evident between the moderate-vigorous intensity protocols. The moderate-vigorous intensity protocols induced significant increases of IL-6, cortisol, and leukocytes in comparison to the low-intensity protocols (P < 0.05). However, the IL-6 response showed no significant differences between the moderate-vigorous intensity protocols, despite the M-VR protocol inducing the largest response of markers indicative of muscle damage (CK, myoglobin, and neutrophil count) (P < 0.05). Hence, indicating a disassociation between the IL-6 response and markers of muscle damage within the respective exercise bouts. The highest IL-6 response was evident in the moderate-vigorous intensity protocols immediately post-exercise. Moreover, the exercise modality did not seem to influence the acute IL-6 and CRP response, with the main determinant of the IL-6 response being exercise intensity.