Post-operative analgesia after total knee arthroplasty (TKA) has always been a challenge in the anesthesiological setting, having to combine good pain control and the need for early mobilization, both factors that can affect the quality of rehabilitation treatment, prosthetic functional outcome, the onset of chronic pain, joint stiffness and the consequent quality of life of the patient. Recent loco-regional anesthesia (LRA) techniques have made an essential contribution to peri-operative management in the fast-track perspective of surgery, in terms of optimization of analgesia and rapid functional recovery. Inadequate post-operative analgesia, by affecting the normal rehabilitation pathway, is associated with medium-long term complications, such as chronic pain, joint stiffness and patient dissatisfaction, which often compromise functional autonomy and quality of life of the patient and may require invasive treatments (surgical revision, unlocking under general anesthesia). The local and systemic inflammatory state, evidenced by peri-operative dosage of specific biomarkers, appears to be related to prosthetic outcome.