Background: Mesenteric lymph node amyloid deposits are rare and may be seen in isolated or secondary amyloidosis. The diagnosis of mesenteric amyloidosis has conventionally relied on histopathological examination following an exploratory laparotomy or a biopsy. Case: A 72-year-old male previously diagnosed with Waldenström’s macroglobulinemia and multiple other malignancies was admitted for abdominal pain. An abdominal computed tomography (CT) scan revealed diffuse retroperitoneal and mesenteric lymphadenopathy associated with bowel wall thickening. A CT-guided fine-needle aspiration (FNA) cytology and core biopsies of mesenteric lymph nodes were performed. The FNA smears revealed irregular, waxy, basophilic clumps on a Diff-Quik stain and cyanophilic clumps of amorphous material on a Papanicolaou stain. The lymph node aspirates showed positivity for the Congo red stain, confirming it as amyloid. In situ hybridization studies revealed a predominance of λ light chains, and a diagnosis of primary amyloidosis involving mesenteric lymph nodes was made. Supplemental needle core biopsies showed positivity for Congo red and Crystal violet stains and exhibited the classic apple-green birefringence under polarized light. Conclusion: The involvement of lymph nodes in amyloidosis is not uncommon; however, the involvement of mesenteric lymph nodes in a setting of macroglobulinemia and its diagnosis by FNA cytology is novel to this case.