The growing number of total joint replacements performed every year has led to an increase in the number of patients experiencing unexplained pain around their joint replacement post-operatively. Infections and implant dislocations are common complications from joint replacement surgery; however, excessive aseptic immune activation in response to implant materials (i.e., metal hypersensitivity to nickel) can also occur and induce painful outcomes, but are more challenging to diagnose. We hypothesize that higher pain levels reported from patients with total joint anthroplasty (TJA) will correlate with a higher degree and incidence of nickel hypersensitivity, as determined by metal lymphocyte transformation testing (metal-LTT). We retrospectively reviewed nickel hypersensitivity results from 209 TJA subjects where infection and mechanical problems have been ruled out and plotted their lymphocyte stimulation index against their self-reported pain levels at the time of the test. TJA patients with no previous history of any allergies with moderate- (4–7 on a scale of 10) and high- (8–10 on a scale of 10) pain scores showed a significantly higher average lymphocyte stimulation index to nickel at 0.1 mM (9.84 and 8.86, respectively), compared to TJA subjects with low-pain (1–3 on scale of 10) levels and to no-pain control subjects (4.98 and 1.8, respectively). Similarly, the incidence of subjects highly reactive to nickel at 0.1 mM was considerably greater in the high-pain group (39 %) compared to the low- and no-pain groups (14 % and 2 %, respectively). Our data shows that elevated lymphocyte reactivity to nickel in low-, moderate-, and high-pain groups compared to the control group lends support for the usefulness of in vitro metal hypersensitivity testing in diagnosing unexplained painful TJA.