Background: Epidemiologic studies of Oral and Maxillofacial lesions (OMLs) are rare compared with the studies of caries and periodontal diseases. It is fundamental to promote early diagnosis and provide appropriate health programs. This study was to investigate the prevalence and distribution of histologically confirmed OMLs in Sana’a.Methodology: The documented records of all patients with OMLs were recovered from the biggest histopathology laboratories that provide biopsy analysis in Sana'a Yemen, for a period of six years (2013 to 2018). This multicenter retrospective study was conducted on 1376 oral and maxillofacial biopsied lesions. The clinico-pathologic data were extracted from the histopathology reports which included age, gender, nature of specimen, site of lesion, clinical appearance and histopathological diagnosis. Descriptive analysis, Chi squared test, and binary logistic regression were performed.Results: Regarding malignant lesions, the most prevalent lesions among males and females was squamous cell carcinoma; OSCC (226; 33.0% and 214; 30.9%; respectively). Followed by undifferentiated pleomorphic sarcoma which were five cases (0.7%) for males and 6 cases (0.9%) for females. Most of the cases (43.8%) diagnosed as OSCC were in the age group older than 40 years old. At this age group, the second most prevalent lesions were Adenocarcinoma and Adenoid cystic carcinoma (0.7% and 0.6%; respectively). The results of the regression analysis show that the site of the lesion (OR; 0.6, CI; 0.51-0.81; P= 0.00) and age of the patient (OR; 4.17, CI; 5.22-5.41; P=0.00) were the independent factors of malignancy of oral lesions.Conclusion: The present study showed high prevalence of malignant and premalignant oral mucosal lesions. The data from this study highlighted the need for dental public health intervention programs for early detection of oral cancer among Yemeni population by dental practitioners. As well as the importance of education of the general population in regards to risk factors of OMLs.