The aim of this study was to investigate the clinicopathologic features of primary intraosseous squamous cell carcinoma arising from an odontogenic keratocyst (PIOSCC ex OKC) and comprehensively improve the understanding of this disease. We retrospectively investigated five cases of PIOSCC ex OKC at Peking University School and Hospital of Stomatology. We also conducted a systematic review of studies on PIOSCC ex OKC by using online databases from their inception until February 2020. In our series of five cases, all lesions were located in the mandible. Three cases (60%) showed recurrent OKCs and two cases (40%) showed primary OKCs. During the follow-up period, one patient died of local relapse. No patients developed metastasis. On the basis of our literature survey, we selected 22 articles reporting 29 patients with PIOSCC ex OKC. Seven of these patients (24.1%) showed local recurrence, three patients (10.3%) developed cervical metastasis, three patients (10.3%) developed distant metastasis (in the pleura in one case and in the lung in two cases), and seven patients died from the disease during the follow-up period. The disease-specific 5-year survival rate in the study group was 53.2%. Through univariate and multivariate analysis, local recurrence was identified as the only significant independent prognostic factor for survival (P < 0.05). The results suggest that PIOSCC ex OKC is a rare intermediate-grade malignancy. Although elective neck dissection is typically unnecessary, adequate therapy should be applied to achieve the lowest local recurrence rate possible to ensure a favorable survival rate.