Objective To explore adverse effects of combined treatment of interleukin-12 (IL-12) and interleukin-18 (IL-18) against cryptococcosis in a murine model. Methods Infected mice were treated with a combination of IL-12 and IL-18. Their body weight and intake of water and food were observed and recorded. Serum levels of leptin were detected with an enzyme-linked immune sorbent assay (ELISA). Results In the combined treatment group, the intake volume of water and food were reduced, leading to weight loss and undetectable levels of leptin in the serum. These adverse effects were more profound in mice that had received higher doses of cytokines, which sometimes led to a fatal outcome. There was a significant difference compared with the control group. Neutralization of endogenous tumor necrosis factor-α (TNF-α) by its specific mAb did not alter the wasting effect of this treatment. Conclusions The combined IL-12/IL-18 treatment may cause a number of adverse effects independent of TNF-α and leptin synthesis. Further investigations for resolving these adverse effects are required before clinical application of these cytokines.