Ameloblastic fibro-odontoma (AFO) is a controversial, rare benign mixed odontogenic tumour that was re-defined as "developing odontoma" in the 2017 WHO classification arguing that once dental hard tissues form, it is programmed to transform into odontoma. However, AFO still remains unclear in terms of its nature. We aimed to analyze a large series of AFOs and compare it to a large series of odontomas (ODs) in an attempt to set cut-off diagnostic parameters between these entities and discuss latest updates on AFO histopathologic, clinical and molecular features. A total of 23 well-documented AFOs were analyzed versus 310 ODs focusing on the age of the patients and size of the lesions. For AFO, mean age was 9.4 +/- 3.9 years (range 3-16 years) and mean size (greatest diameter) was 2.9 +/- 1.5 cm (range 0.8-5.5 cm). For OD-mean age was 26.5 +/- 15.6 years (range 3-81 years), mean size 1.9 +/- 0.9 cm (range 1-5 cm). Receiver operating curve (ROC) showed that a cut-off age of 13.5 years and below [area under the curve (AUC) 0.902, 95%CI 0.859-0.945; p < 001; sensitivity 80%, specificity 87%] and a cut-off size of 2.1 cm and above are likely to be associated with AFO (AUC 0.7, 95%CI 0.574-0.827; p = 0.001; sensitivity 57%, specificity 77%). Thus, the combination of age and lesion size may be used to distinguish between lesions of a true neoplastic nature (i.e., AFO) and hamartomatous formation (i.e., OD). Further molecular and genetic specifications are needed to provide a better understanding on the pathogenesis of AFO in support of our suggestion and aid in an accurate classification of AFO.