How lymphocyte-mediated metal sensitivity affects orthopaedic implant performance remains poorly understood. Do patients with implants exhibit elevated lymphocyte reactivity to metals and is this reactivity more generalized or more implant-alloy specific? We investigated these questions by measuring lymphocyte responses to implant metals (Cr(+3), Co(+2), Ni(+2) at 0.1mM, and Ti(+4) at 0.001 mM) in six subject groups: Group 1a=young controls, Group 1b=age matched controls, Group 2a=subjects with osteoarthritis (OA) and no history of metal sensitivity, Group 2b=OA subjects with history of metal sensitivity, Group 3a=total hip arthroplasty (THA) subjects with no to mild radiographic osteolysis, and Group 3b=THA subjects with moderate osteolysis. Lymphocyte proliferation, using Lymphocyte Transformation Testing (LTT), and cytokine release provided quantitative reactivity measurement, where a stimulation index of >2 indicated metal sensitivity. OA subjects with a history of metal sensitivity (Group 2b) were more metal reactive to Ni than any other group, as expected (66% incidence and Stimulation Index >20). However, THA subjects (Groups 3a and b) were >3 fold more reactive to Cr (p<0.04), than were controls (Groups 1a & b) or OA subjects (Groups 2a & b). THA subjects with moderate vs mild osteolysis (Group 3b vs 3a) were more reactive to Co (43% vs 0% incidence). Only osteolytic THA subjects demonstrated increased cytokine responses with >two-fold (p<0.05) increases in soluble interferon-gamma (IFN-gamma) and interleukin-2 (IL-2) levels in response to Cr challenge. This elevated incidence and averaged level of lymphocyte reactivity supports a metal-specific adaptive immune response and suggests involvement in the pathogenesis of poor implant performance, e.g. aseptic osteolysis.