Background: The definite diagnosis of thalassemia is based upon relatively complex laboratory tests, hence, these syndromes might be underestimated in the routine clinical setting. Methods: 500 consecutive individuals identified in Laboratorios Clinicos de Puebla with red blood cells showing either hypochromia (MCH<24 pg) and/or microcytosis (MCV <75 fl in women or <80 fl in man), with or without anemia, were prospectively accrued in this study, along a 16 month-period. Iron deficiency, β and α-thalassemia were searched by definite methods. Results: Out of the 500 consecutive cases with red blood cell hypochromia or microcytosis, 394 (78.8%) were found to have iron deficiency, 37 cases had β-thalassemia, 11 cases had a-thalassemia, while in 58 cases (11.6%) a definite diagnosis could not be established. Red cell distribution width (RDW) was significantly lower in the thalassemic patients than in the iron deficient group, and it proved to bear high nosographic sensitivity and specificity for the diagnosis of either α or β thalassemia. Conclusions: The thalassemic syndromes should be suspected in individuals with red blood cell microcytosis and / or hypochromia, with or without anemia, showing very low RDW values. These individuals should be further tested for thalassemia.