Abstract Two cases, the first reported in the medical literature, of association of the hemoglobin "Pylos" anomaly and hemoglobin S are discussed. The clinical picture and laboratory findings are presented, and the difficulty of accurate diagnosis by the routine procedures of hemoglobin analysis is emphasized. The findings are discussed in relation to observations on the behavior of this anomalous hemoglobin in the presence of hemoglobin A and thalassemia.