Knee osteoarthritis (OA) is a chronic degenerative inflammatory-based condition caused by a cascade of different intra-articular molecules including several cytokines. Among the cytokines, prokineticins (PKs) have recently been identified as important mediators of inflammation and pain. This observational study examined the potential involvement of PK2 in degenerative or traumatic knee disease. Fifteen patients presenting knee osteoarthritis (OA group) and 15 patients presenting a traumatic meniscal tear (TM group) were studied. Synovial fluid samples from affected knees were assessed for PK2, IL-10, and TNF-α using the ELISA method. At a long-term follow-up (minimum 5 years, mean = 6.1 years), patients in the TM group underwent clinical re-evaluation with PROMs (Tegner Activity Scale, IKDC, Lysholm, SKV); in addition, X-ray visualization was used to assess the presence of secondary OA. PK2 was detected in synovial fluids of both TM and OA patients and the levels were comparable between the two groups, while IL-10 levels were significantly greater in the OA group than those in TM patients. PK2 levels correlated with those of IL-10. PK2 levels were greater in blood effusions compared to clear samples, did not differ significantly between sexes, nor were they related to differences in weight, height, or injury (meniscal laterality, time since dosing). No correlation was found between PROMs and radiological classifications in patients in the TM group at final follow-up. These data are the first observations of PK2 in synovial fluid following traumatic meniscus injury. These findings suggest possible further prognostic indices and therapeutic targets to limit the development of secondary OA.