Introduction Passive elevation of body temperature can induce an acute inflammatory response that has been proposed to be beneficial for metabolic health. However, the heat strain associated with whole-body heating can be perceived as uncomfortable. While implementing local cooling strategies may partly alleviate thermal discomfort during passive heating, it is not known how such protocol adaptations impact on the acute inflammatory response. The aim of this series of studies was to investigate the effect of local cooling strategies on the acute inflammatory response to passive heating. Methods Study 1 Using a water-perfused suit, ten recreationally active males underwent three 90 min conditions: heating of the legs (50°C water) with upper-body cooling (2°C water and ice packs; LBH), whole-body heating (50°C water; WBH) and exposure to a thermoneutral temperature (36°C water; CON). Blood samples were collected before and up to 3h post-session to assess inflammatory markers. Rectal temperature, basic affect and thermal comfort were recorded at regular intervals. Study 2 Nine recreationally active male participants were immersed up to the waist for three 60 min water immersion conditions: 42°C hot water immersion (HWI), 42°C HWI with simultaneous upper-body cooling using a fan (FAN), and 36°C thermoneutral water immersion (NEU). Blood samples to determine interleukin (IL)-6 plasma concentration were collected pre- and post-water immersion; rectal temperature, basic affect and thermal comfort were assessed throughout the intervention. Results Study 1 The IL-6 incremental area under the curve (iAUC) was higher for LBH (1096±851 pg/mL*270min) and WBH (833±476 pg/mL*270min) compared with CON (565±325 pg/mL*270min; p<0.047). Rectal temperature was elevated to a larger extent in WBH (38.6±0.4°C) compared with the other trials (p<0.001), and was higher at the end of LBH (37.1±0.3°C) compared with CON (36.7±0.2°C, p=0.001). Basic affect and thermal comfort were more negative during WBH compared with LBH and CON (p<0.010). Study 2 Plasma IL-6 concentration was higher for HWI and FAN when compared with CON (p<0.001) and did not differ between HWI and FAN (p=0.221; pre to post, HWI: 1.0±0.6 to 1.5±0.7 pg/mL, FAN: 0.7±0.5 to 1.1±0.5 pg/mL, CON: 0.5±0.2 to 0.5±0.2 pg/mL). Rectal temperature was elevated to a larger extent in HWI (38.7±0.6°C) compared with FAN and NEU (p<0.001), and was higher in FAN (38.1±0.4°C) compared with NEU (37.1±0.3°C, p<0.001). At the end of immersion, basic affect was lowest for HWI (HWI: -1.8±2.0, FAN: 0.2±1.6, CON 1.0±2.1, p<0.020); thermal comfort for HWI was changed from pre into the uncomfortable range (3.0±1.0, p<0.001), whereas FAN (0.7±0.7, p=0.160) and CON (-0.2±0.7, p=0.283) remained in the comfortable range throughout. Conclusions Both aggressive upper-body cooling through a water-perfused suit and ice packs (study 1) as well as modest cooling using a fan (study 2) resulted in more positive perceptual responses compared with whole-body heating. Moreover, although LBH attenuated the response in additional cardiometabolic markers, both LBH and FAN did not attenuate the acute IL-6 response. The use of a fan may thus be considered as a practical and low-cost tool to enhance the tolerability of passive heating.