Blood marker concentrations such as cortisol (COR) and interleukin (IL)-6 are commonly used to evaluate the physiological strain associated with work in the heat. It is unclear, however, if hot environments of an equivalent thermal stress, as defined by a similar wet bulb globe temperature (WBGT), result in similar response patterns. This study examined markers of neuroendocrine (COR) and immune (IL-6) responses, as well as the cardiovascular and thermal responses, relative to changes in body heat content measured by whole-body direct calorimetry during work in two different hot environments with equivalent WBGT. Eight males performed a 2-hr heavy intermittent exercise protocol (six 15-min bouts of cycling at a constant rate of metabolic heat production (360W) interspersed by 5-min rest periods) in Hot/Dry (46°C, 10% relative humidity [RH]) and Warm/Humid (33°C, 60% RH) conditions (WBGT ∼ 29°C). Whole-body evaporative and dry heat exchange, change in body heat content (ΔH(b)), rectal temperature (T(re)), and heart rate were measured continuously. Venous blood was obtained at rest (PRE) and the end of each exercise bout for the measurement of changes in plasma volume (PV), plasma protein (an estimate of plasma water changes), COR, and IL-6. Ratings of perceived exertion and thermal sensation were measured during the last minute of each exercise bout. No differences existed for ΔH(b), heart rate, T(re),%ΔPV, plasma protein concentration, perceptual strain (thermal sensation, perceived exertion), and COR between the Hot/Dry and Warm/Humid conditions. IL-6 exhibited an interaction effect (p = 0.041), such that greater increases were observed in the Hot/Dry (Δ = 1.61 pg·mL(-1)) compared with the Warm/Humid (Δ = 0.64 pg·mL(-1)) environment. These findings indicate that work performed in two different hot environments with equivalent WBGT resulted in similar levels of thermal, cardiovascular, and perceptual strain, which support the use of the WBGT stress index. However, the greater IL-6 response in the Hot/Dry requires further research to elucidate the effects of different hot environments and work intensities.