Though common in older adults, anaemia is unexplained in about one-third of cases. As a rare cause of anaemia and neutropenia, Cu deficiency could account for some cases of unexplained anaemia. We examined the relationship between serum Cu and unexplained anaemia among 11,240 participants in the Second National Health and Nutrition Examination Survey (NHANES II): 638 (5.7% of all adults) were anaemic; 421 (3.7%) were not explained by deficiencies of vitamin B12, folate or Fe, chronic illness or renal disease. Spline regression showed a U-shaped relationship between serum Cu levels and unexplained anaemia, indicating that both high and low serum Cu levels are associated with unexplained anaemia in adults. Chronic inflammation and mild Fe deficiency could account for the association between unexplained anaemia and elevated Cu levels. On the other hand, the finding of hypocupraemia in a subset of adults with unexplained anaemia suggests that Cu deficiency may be a common reversible cause of anaemia in adults.