Atypical patterns of response to immunotherapy have been observed, including the abscopal effect and pseudoprogression. Although both are infrequent in head and neck squamous cell carcinoma, the synergism between radiation and checkpoint blockade therapy has generated excitement for exploitation of the abscopal effect. However, robust abscopal tumor regression observed in preclinical models has not translated to clinical experience. The optimal sequencing of radiotherapy with immunotherapy and dosage of radiation to target lesions to elicit this effect is being explored in clinical trials. Predictive markers of efficacy must be studied further to identify patients who may benefit from an abscopal effect and continued checkpoint inhibitor blockade beyond initial signs of radiologic progression. Given the rarity of pseudoprogression in head and neck squamous cell carcinoma, patients should be carefully selected to continue on immunotherapy, despite early radiologic signs of progression, given the risk of aggressive true progression and clinical deterioration that may result in missed opportunities for alternate treatments.