Topical therapeutic options for cutaneous squamous cell carcinoma in situ include 5-fluorouracil cream and imiquimod cream. Such treatment may be preferable to surgical or destructive modalities in certain anatomic locations and in instances where patients are unwilling or poor surgical candidates. We present 4 such patients with cutaneous squamous cell carcinoma in situ involving a digit. Each patient failed treatment with imiquimod cream as monotherapy. In addition, two patients failed treatment with 5-fluorouracil cream as monotherapy. All 4 responded completely to 5-fluorouracil and imiquimod cream as combination therapy. In patients who have failed monotherapy with a topical agent for cutaneous squamous cell carcinoma in situ, combination treatment using both topical 5-fluorouracil cream and imiquimod cream may be considered as an alternative therapeutic strategy.