In earlier work, we reported that genetically obese (fa/fa) Zucker rats exhibited significantly greater anorexia than did lean (Fa/Fa) Zucker rats to intracerebroventricular infusion of interleukin (IL)-1beta. Here, we investigated the fever response of obese (fa/fa) and lean (Fa/Fa) Zucker rats to intracerebroventricular microinfusion of IL-1beta as well as to the following other cytokines: IL-2, IL-6, and tumor necrosis factor-alpha (TNF-alpha). Core body temperature was monitored by a radiotelemetry system in freely moving rats. The results show that 1) both IL-1beta and IL-6 induce fevers in obese and lean rats; 2) IL-1beta induces a significantly higher fever response in obese rats than it does in lean rats; 3) IL-6 induces a significantly higher fever response in lean rats than it does in obese rats; 4) IL-2 induces a moderate fever response in lean but not obese rats; 5) TNF-alpha induces a similar fever response in obese and lean rats; and 6) the fevers induced by each effective cytokine have different time courses. Thus obese (fa/fa) and lean (Fa/Fa) Zucker rats show differential responsiveness to the intracerebroventricular microinfusion of various classes of cytokines. This suggests that genetic obesity in the fa/fa Zucker rat is associated with differential cytokine action on thermoregulatory mechanisms.