Abstract: Aspartame (APM) is one of the most widely used artificial sweeteners in the world. Its ever-growing use in more than 6000 products, such as soft drinks, chewing gum, candy, desserts, etc., has been accompanied by rising consumer concerns regarding its safety, in particular its potential long-term carcinogenic effects. In light of the inadequacy of the carcinogenicity bioassays performed in the 1970s and 1980s, a long-term mega-experiment on APM was undertaken at the Cesare Maltoni Cancer Research Center of the European Ramazzini Foundation on groups of male and female Sprague-Dawley rats (100–150/sex/group), 8 weeks old at the start of the experiment. APM was administered in feed at concentrations of 100,000, 50,000, 10,000, 2,000, 400, 80, or 0 ppm. Treatment lasted until spontaneous death of the animals. The results of the study demonstrate that APM causes: (a) an increased incidence of malignant tumor-bearing animals, with a positive significant trend in both sexes, and in particular in females treated at 50,000 ppm (P≤ 0.01) when compared to controls; (b) an increase in lymphomas–leukemias, with a positive significant trend in both sexes, and in particular in females treated at doses of 100,000 (P≤ 0.01), 50,000 (P≤ 0.01), 10,000 (P≤ 0.05), 2000 (P≤ 0.05), and 400 ppm (P≤ 0.01); (c) a statistically significant increased incidence, with a positive significant trend, of transitional cell carcinomas of the renal pelvis and ureter in females and particularly in those treated at 100,000 ppm (P≤ 0.05); and (d) an increased incidence of malignant schwannomas of the peripheral nerves, with a positive trend in males (P≤ 0.05). The results of this mega-experiment indicate that APM, in the tested experimental conditions, is a multipotential carcinogenic agent.