To our knowledge, this is the first blind and controlled analysis of subcutaneous fat aspiration for the diagnosis of primary systemic amyloidosis. The procedure was performed on 82 patients with biopsy-proved systemic amyloidosis and 72 normal adult volunteers. Slides from 71 of the 72 controls were read as negative. Slides from 59 (72%) of the 82 patients with amyloidosis were read as positive or weakly positive after staining with alkaline Congo red. Subcutaneous fat aspiration was as sensitive as rectal biopsy and substantially more sensitive than bone marrow biopsy in diagnosing amyloidosis. In six instances fat aspiration would have obviated the need for a more invasive diagnostic biopsy. Subcutaneous fat aspiration is sensitive (72%) and specific (99%) for amyloidosis. It is technically simpler and less expensive than rectal biopsy and permits immediate assessment of specimen adequacy. The concordance rate for two independent pathologists was 95%. Equivocally positive stains should be interpreted with caution because weak nonspecific staining may be seen.