The pathway of pain in the anterior knee pain syndrome remains unclear. It has been hypothesized that some biochemical mediators of inflammation, such as cytokines contribute to the process. The objective of this work was to evaluate the synovial membrane and the infrapatellar fat pad expression of the inflammatory mediators and potentially chondrodestructive cytokines interleukin 6 (IL-6) and tumour necrosis factor α (TNF-α) in the anterior knee pain syndrome, and to determine whether the cytokine expression counterpart with/corresponds to the amount of chondral damage in this syndrome. Ten consecutive patients with the anterior knee pain syndrome (group I) participated in the study. Patients with a history of trauma were excluded from this group. For comparison we used 10 patients with anterior cruciate ligament rupture or meniscal lesion with no history of pain in the anterior compartment (group II). Immunohistochemical techniques using a polyclonal rabbit anti-human antibody to IL-6 and a monoclonal mouse anti-human antibody to TNF-α were employed. The results show a statistically significant higher expression of IL-6 in infrapatellar fat pad (p < 0.05) as well as TNF-α in the infrapatellar fad pad and the synovium (p < 0.03, and p < 0.02, respectively) in group I as compared to control subjects. There is no any difference in the amount of chondral damage present in group I as compared to group II. The results of this study provide the immunohistochemical evidence suggesting that the anterior knee pain syndrome could be characterized by infrapatellar fat pad and synovial inflammation variations without the articular cartilage loss.