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We initially hypothesized that metal\u2010induced lymphocyte proliferation responses to soluble metal challenge (ions) are mediated exclusively by early T\u2010cell activation (not B\u2010cells), typical of a delayed\u2010type\u2010hypersensitivity response. We tested this by comparing proliferation (6 days) of primary lymphocytes with early T\u2010cell and B\u2010cell activation (48 h) in three groups of subjects likely to demonstrate elevated metal reactivity: group 1 (<jats:italic>n<\/jats:italic> = 12) history of metal sensitivity with no implant; group 2a (<jats:italic>n<\/jats:italic> = 6) well performing metal\u2010on\u2010metal THRs, and group 2b (<jats:italic>n<\/jats:italic> = 20) subjects with poorly performing metal\u2010on\u2010polymer total joint arthroplasties (TJA). Group 1 showed 100% (12\/12) metal reactivity (stimulation index &gt; 2) to Ni. Groups 2a and 2b were 83% (5\/6) and 75% (15\/22) metal reactive (to Co, Cr, or Ni), respectively. Of the <jats:italic>n<\/jats:italic> = 32 metal\u2010reactive subjects to Co, Cr, or Ni (SI &gt; 2), <jats:italic>n<\/jats:italic> = 22\/32 demonstrated &gt;2\u2010fold elevations in % of T\u2010cell or B\u2010cell activation (CD25+, CD69+) to metal challenge when compared with untreated control. 18\/22 metal\u2010activated subjects demonstrated an exclusively T\u2010cell or B\u2010cell activation response to metal challenge, where 6\/18 demonstrated exclusively B\u2010cell activation and 12\/18 demonstrated a T\u2010cell only response, as measured by surface activation markers CD25+ and CD69+. However, there was no direct correlation (<jats:italic>R<\/jats:italic><jats:sup>2<\/jats:sup> &lt; 0.1) between lymphocyte proliferation and % T\u2010cell or B\u2010cell activation (CD25+:CD69+). Proliferation assays (LTT) showed greater ability to detect metal reactivity than did subject\u2010dependent results of flow\u2010cytometry analysis of T\u2010cell or B\u2010cell activation. The high incidence of lymphocyte reactivity and activation indicate that more complex than initially hypothesized immune responses may contribute to the etiology of debris\u2010induced osteolysis in metal\u2010sensitive individuals. \u00a9 2009 Wiley Periodicals, Inc. 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