AbstractBackgroundSpontaneous regression (SR) of cancer is an exceedingly rare phenomenon. While SR is well‐documented for some cancers, very few reports exist in oropharyngeal squamous cell carcinomas (OPSCCs) and none in human papillomavirus (HPV)‐positive OPSCCs.MethodsA 67‐year old man presented with a left‐sided neck mass. Neck CT, PET, and biopsies showed a SCC in a left‐sided lymph node without a primary lesion. Immunohistochemistry confirmed HPV16. Six weeks after biopsy, the patient underwent left selective tonsillectomy and neck dissection.ResultsSurgery revealed a left tonsillar SCC and no lymph nodes with tumor. Histology revealed homogenous fibrosis and intermixed immune cells indicative of tumor regression analogous to reports of immune‐related pathologic responses. AE1/AE3 immunostain was also negative for tumor. All lymph nodes remained negative at 1 year follow‐up.ConclusionWe described a spontaneously regressed lymph node in a tonsillar HPV‐positive SCC. The unique immune environment of HPV‐positive OPSCCs, and unknown environmental or host factors, may have played a role in our patient's SR which requires future studies to elucidate.