The role of interleukin-6 (IL-6) on emotional behavior was studied in two experiments using transgenic mice carrying a null mutation for IL-6 (IL-6(-/-)). In the first experiment, IL-6(-/-) mice were compared with the two wild-type strains contributing to the genetic background of the transgenic mice, namely C57BL/6J and 129/SvJ, as well as with the F2 offspring of C57BL/6J x 129/SvJ mice. The two parental strains differed substantially in terms of emotional reactivity, suggesting that the F2 offspring were more appropriated for analyzing the effect of the null mutation. IL-6(-/-) mice showed lower levels of ambulation in the holeboard, and lower levels of exploration of the open arms of the plus-maze, than the wild-type F2 C57BL/6J x 129/SvJ mice. In the second experiment, IL-6(-/-) mice were backcrossed for 10 generations to C57BL/6J mice to decrease the uncertainty of the effect of the genetic background, and when compared with wild-type C57BL/6J mice in the holeboard and the plus-maze, the same results were obtained. Therefore, IL-6(-/-) mice seem to be more emotional than their appropriate controls, suggesting that the major cytokine IL-6 is involved in the control of emotionality.