Aspartame is a synthetic sweetener that has been used safely in food for more than 30 years. Its safety has been evaluated by various regulatory agencies in accordance with procedures internationally recognized, and decisions have been revised and updated regularly. The present review summarizes the most relevant conclusions of epidemiological studies concerning the use of low-calorie sweeteners (mainly aspartame), published between January 1990 and November 2012. In the Nurses' Health study and the Health Professionals Followup study some excess risk of Hodgkin lymphoma and multiple myeloma was found in men but not in women; no association was found with leukemia. In the NIH-AARP Diet and Health Study, there was no association between aspartame and haematopoietic neoplasms. US case-control studies of brain and haematopoietic neoplasms also showed no association. The NIH-AARP Diet and Health Study and case-control studies from California showed no association with pancreatic cancer, and a case-control study from Denmark found no relation with breast cancer risk. Italian case-control studies conducted in 1991-2008 reported no consistent association for cancers of the upper aerodigestive tract, digestive tract, breast, endometrium, ovary, prostate, and kidney. Low calorie sweeteners were not consistently related to vascular events and preterm deliveries.