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Clonality testing using BIOMED-2-based multiplex PCR is widely applied in routine diagnostics, but its interpretation can be complicated by clonal-like peaks arising from non-neoplastic immune responses. In this study, we retrospectively analyzed routine diagnostic cases examined by IGH and TCRB multiplex PCR and assessed both the number of rearranged regions and peak patterns in B-cell lymphoma (N = 291), T-cell lymphoma (N = 48), Classic Hodgkin lymphoma (N = 31), reactive lymphoid hyperplasia (N = 28), and carcinoma (N = 41). The most clinically relevant finding was the frequent detection of apparent IGH clonality in carcinoma, often accompanied by polyclonal background. Clonal IGH peaks were detected in 16 of 35 carcinoma cases (46%), including 7 of 35 cases (20%) with peaks in two or more regions. Among these 16 cases, 11 (69%) showed polyclonal background. In contrast, reactive lymphoid hyperplasia showed much lower IGH positivity, with clonal peaks in 3 of 25 cases (12%) and only 1 of 25 cases (4%) with peaks in two or more regions. More informative than lineage-associated positivity itself were the disease-specific peak patterns, especially the frequent appearance of clonal-like IGH peaks with polyclonal background in carcinoma and the background-rich patterns seen in T-follicular helper cell lymphoma, angioimmunoblastic type/angioimmunoblastic T-cell lymphoma (AITL). These findings indicate that BIOMED-2 clonality assays capture not only neoplastic clones but also disease-specific immune background. Frequent IGH peaks with polyclonal background in carcinoma represent an important diagnostic pitfall and should be interpreted carefully together with the pathological and immunohistochemical results.