Squamous cell carcinoma (SCC) developing in lesions of discoid lupus erythematosus (DLE) is rare, most frequently arising on sun-exposed skin and very rarely affecting the lips. A review of the English language literature revealed only 21 published cases of labial SCC in patients with DLE. Here, an unusual case of a patient with DLE who developed 3 primary SCCs of the oral and perioral region is presented. A 40-year-old female with a 24-year history of DLE with peri- and intraoral involvement initially developed SCC of the vermillion border of the right lower lip; the lesion was surgically removed and did not recur within 6 months. In spite of strong recommendation for regular follow-up, the patient failed to keep her appointments but returned 7 years later. No signs of recurrence of the original lower lip cancer were noticed, but a new SCC of the left lateral border of the tongue with cervical lymph node metastasis was diagnosed; despite aggressive combined treatment, locoregional recurrence and distant metastatic disease developed within a few months; in addition, a new primary SCC of the vermillion border of the left lower lip developed. This rare case and a thorough review of the pertinent literature underscore the possibility of development of even multiple intraoral and perioral SCCs in the context of longstanding DLE, which necessitates close long term follow-up for early diagnosis and management.