Due to their mechanical properties, there has been growing interest in poly-ether-ether-ketone (PEEK) and its composites as bearing material in total and unicompartmental knee arthroplasty. The aim of this study was to analyze the biological activity of wear particles of two different (pitch and PAN) carbon-fiber-reinforced- (CFR-) PEEK varieties in comparison to ultra-high-molecular-weight-polyethylene (UHMWPE) in vivo. The authors hypothesized no difference between the used biomaterials. Wear particle suspensions of the particulate biomaterials were injected into knee joints of Balb/c mice, which were sacrificed after seven days. The cytokine expression (IL-1β, IL-6, TNF-α) was analyzed immunohistochemically in the synovial layer, the adjacent bone marrow and the articular cartilage. Especially in the bone marrow of the two CFR-PEEK varieties there were increased cytokine expressions compared to the control and UHMWPE group. Furthermore, in the articular cartilage the CFR-PEEK pitch group showed an enhanced cytokine expression, which could be a negative predictor for the use in unicondylar knee systems. As these data suggest an increased proinflammatory potential of CFR-PEEK and its composites in vivo, the initial hypothesis had to be refuted. Summarizing these results, CFR-PEEK seems not to be an attractive alternative to UHMWPE as a bearing material, especially in unicompartmental knee arthroplasty.