Proinflammatory cytokines, for example interleukin (IL-)6, are discussed as biomarkers for neuropsychiatric disorders such as anxiety disorders. However, it is not clear whether IL-6 may cause a dysregulation of emotional behaviors observed in posttraumatic stress (PTSD) and other anxiety disorders. Fear conditioning is a widely used paradigm to model memory-related features of PTSD in mice. We therefore tested auditory-cued fear memory features in male and female IL-6 knockout mice. We observed a reduced generalization of fear memory towards a non-conditioned tone, especially in female IL-6 knockout mice. This was associated with a trend for reduced short-term fear memory as well as increased extinction. After behavioral testing, expression levels of plasticity-relevant factors were analyzed in micropunches of the basolateral amygdala and the dentate gyrus (DG) and CA1 of the dorsal hippocampus via qPCR. In the DG, mRNA levels of the vesicular transporter for GABA (vGAT), were elevated in IL-6 knockout mice regardless of their sex. mRNA levels for neuropeptide Y, a resilience associated factor, were reduced specifically in the DG of male IL-6 knock out mice, along with an increased expression of its receptor Y1 but not Y2. In the CA1, the expression of glucocorticoid was elevated in male and female IL-6 deficient animals, but the serum levels of its substrate corticosterone were higher in females compared to males. Together, IL-6 deficiency may prevent generalization of fear memory in a mouse model, especially in females. This may relate to altered hippocampal expression profiles of molecular markers related to stress processing.