Keratoacanthoma (KA) is an epithelial tumor of the skin, classically considered as having a malignant transformation risk of 15%; however, many authors and the new World Health Organization (WHO) Classification of skin tumors consider KA as an incipient variant of the cutaneous squamous cell carcinoma (SCC). The aims of the study were to assess the clinical, histopathological (HP) and immunohistochemical (IHC) aspects of the KA and the role of these factors in malignancy occurrence. The studied group comprises 194 patients diagnosed with KA or malignant KA, hospitalized in the Clinic of Dermatology, Emergency County Hospital, Craiova, Romania, between 2006 and 2019. There were 83 males and 111 females, aged 34 to 90 years, 57.21% of the patients being from the rural environment. The histopathology diagnosed 51 KAs and 143 malignant KAs (SCCs). Clinical diagnosis had a limited value in detecting the absence or presence of malignancy in the KA lesion, due to a low accuracy (36.08% and 29.89%, respectively) and specificity (23.07% and 27.02%, respectively); therefore, the HP exam of the surgical excision specimen has a paramount importance in establishing the diagnosis. IHC analysis revealed that the immunostainings for apoptosis-associated proteins and keratinocyte proliferative activity [p53, B-cell lymphoma-2 (Bcl-2), Ki-67 and proliferating cell nuclear antigen (PCNA)] provide some arguments to differentiate between KA and SCC in the studied cases. The correlation of clinical, HP and IHC data lead to an accurate diagnosis of KA; moreover, the clinical, HP and IHC data sustain the idea that KA is a particular form of well-differentiated SCC, which require an active therapeutic attitude.