Acute mental stress elicits increases in plasma cytokine concentrations in humans, but the underlying mechanisms remain poorly understood. We assessed the impact of beta-adrenergic blockade on plasma interleukin 6 (IL-6) and IL-1 receptor antagonist (IL-1Ra) responses in a parallel group, double-blind randomised placebo-controlled trial involving 64 healthy young adult volunteers. Participants were administered 80 mg slow-release propranolol or placebo daily for 7 days before the stress testing session in which responses to 3 behavioural challenges (public speaking, mirror tracing, mental arithmetic) were evaluated. Propranolol administration was associated with reduced baseline levels of heart rate and IL-1Ra, and systolic blood pressure (BP) in men. Tasks stimulated increased plasma IL-6 concentrations sampled 45 min and 75 min after challenge, but these responses were blocked by propranolol in men (p < 0.001). Propranolol did not influence IL-6 responses in women, or IL-1Ra in either sex. Blood pressure and heart rate increased markedly during the tasks, but there was no differential stress reactivity in propranolol and placebo conditions. The results of the study support a role of sympathetic nervous system activation in stimulating acute IL-6 responses to stress, but only in men. The reasons for the differences between men and women remain to be resolved.