Whilst it is widely recognized that systemic interleukin-6 (IL-6) concentrations increase as a consequence of prolonged exercise, confusion exists over the plasma IL-6 response to exercise with additional heat stress, since the heat may (Brenner et al. 1999) or may not (Niess et al. 2003) augment circulating levels. Recently Rhind and colleagues concluded that the exercise-induced elevation in core temperature “appears to be an important physiological mechanism triggering the hormone–cytokine axis” (Rhind et al. 2004). Therefore, the purpose of the present investigation was to clarify a) if the addition of heat stress augments the IL-6 response to exercise, and b) whether there is an associated neuroendocrine response during exercise in the heat. Following Local Ethics Committee approval and having obtained informed consent, eight non-heat acclimated males (26 ± 8 years, VO₂max: 60 ± 7 ml kg^-1 min^-1, Wmax: 339 ± 34 W) each performed two 60-min bouts of cycling at 70 ± 2% VO₂max at either 20°C (CON) or 35°C (HOT), in a balanced cross-over design. Data were analysed using analysis of variance with repeated measures for time, Tukey’s honestly significant difference post hoc procedure and paired samples t-tests where appropriate. All eight subjects reported exercise as more difficult during HOT than CON, as evidenced by significantly higher ratings of perceived exertion (13.8 ± 0.5 versus 12.6 ± 0.5; p < 0.01). The rise in oesophageal temperature was greater during HOT than CON (p < 0.05), increasing by 1.8°C and 1.2°C, respectively. Plasma levels of IL-6 increased approximately twice as much in the HOT condition than CON (3.7 ± 0.6 versus 1.7 ± 0.2 pg ml^-1; p < 0.05). Concentrations of growth hormone were significantly higher during HOT than CON (91 ± 9 versus 58 ± 8 mU l^-1; p < 0.05) as were concentrations of prolactin (728 ± 145 versus 316 ± 50 mU l^-1; p < 0.01). Estimated total carbohydrate (HOT: 119 ± 22 g, CON: 112 ± 20 g) and fat oxidation (HOT: 57 ± 10 g, CON: 60 ± 11 g) were similar between trials (both p > 0.05). The present results confirm the additive effect of heat stress to the IL-6 response during exercise (Brenner et al. 1999; Rhind et al. 2004). It is unlikely that this response is related to fuel selection, as whole-body carbohydrate and fat oxidation were similar between conditions. Rather, the greater rise in core temperature during HOT was accompanied by significantly higher levels of growth hormone and prolactin, supporting a role for neuroendocrine regulation of exercise-induced IL-6 (Rhind et al. 2004).