The purpose of this investigation was to identify if serum interleukin (IL)-10 and tumor necrosis factor (TNF)-α concentrations and their ratio (IL-10/TNF-α) are altered in subjects predisposed to developing knee osteoarthritis following ligamentous injury and in those with severe knee osteoarthritis. Serum IL-10 and TNF-α concentrations were measured in four groups of subjects (n = 218): (1) reportedly-healthy and non-injured control subjects (CON; n = 92), (2) subjects scheduled to undergo anterior cruciate ligament surgery (ACL; n = 42), (3) non-surgical subjects with knee osteoarthritis (OA; n = 60), and (4) subjects with knee osteoarthritis scheduled to undergo total knee arthroplasty (TKA; n = 24). X-ray images were used to grade the severity of knee osteoarthritis. Serum IL-10 and the serum IL-10/TNF-α ratio were significantly lower while serum TNF-α was not significantly perturbed with severe compared to moderate knee osteoarthritis (i.e., Kellgren-Lawrence grade 4 vs. 3, respectively). Serum IL-10 was significantly lower in the absence of serum TNF-α alterations in the ACL group. We conclude that serum IL-10 concentrations are compromised in subjects predisposed to developing knee osteoarthritis following ligamentous trauma and in subjects with radiographic evidence of severe knee osteoarthritis.