<p>Context: In situ hybridization (ISH) for kappa and lambda immunoglobulin light chains is an important ancillary tool for identifying monoclonal plasma cell or B-cell infiltrates in kidney biopsies. We observed that kidney biopsy cores transported in Michel transport medium (MTM) showed markedly diminished or absent kappa and lambda ISH signals compared with their formalin-fixed counterparts. Objective: To evaluate the effect of MTM fixation on kappa and lambda ISH signal intensity in kidney biopsy specimens. Design: We retrospectively identified kidney biopsies in which tissue was received in both MTM and formalin and for which kappa/lambda ISH was performed. ISH signal intensity was semiquantitatively scored (0–3+) in MTM-fixed and formalin-fixed tissue. Paired comparisons were performed to assess the impact of fixative type and duration of MTM exposure. Results: Among 204 kidney biopsies where ISH was performed, 38 biopsies contained at least one MTM-preserved core that had subsequently been transferred to formalin and embedded within the same paraffin block as a formalin-fixed core. MTM-fixed tissue demonstrated a significant reduction in ISH signal intensity for both kappa and lambda compared with formalin-fixed tissue (p &lt; 0.001). In several cases, ISH signals were completely absent in MTM-fixed tissue despite strong signals in formalin-fixed cores from the same biopsy. Longer MTM exposure correlated with further signal loss. Conclusions: MTM fixation significantly diminishes or abolishes kappa and lambda ISH signals in kidney biopsy specimens. This effect increases with longer exposure times. Awareness of this pitfall is essential, particularly in small biopsies or cases where the only cortex available for ISH is MTM-fixed. When monoclonality assessment is clinically important, formalin-fixed tissue should be prioritized for ISH studies.</p>