Purpose: To evaluate the efficacy and safety of topical 5% fluorouracil (5-FU) cream in the treatment of periocular actinic keratosis and squamous cell carcinoma in situ. Methods: A retrospective case series including 14 patients treated with topical 5-FU cream, 13 patients with actinic keratosis and 1 patient with squamous cell carcinoma in situ. All patients were treated with an initial 2-week course of twice-daily 5-FU application followed by mild ophthalmic antibiotic ointment applied until the epithelium healed. Additional 14-day courses of therapy were prescribed as clinically indicated if residual lesion was present or recurrence occurred. Charts were reviewed for location of lesion, marginal involvement, residual lesion at follow up, recurrence, and ocular adverse events. Results: Six patients had upper eyelid lesions and 8 patients' lesions involved the lower eyelid. Marginal involvement was seen in 9 patients. All patients completed an initial 14-day course of twice-daily therapy. Five patients with actinic keratosis required a second 14-day course of therapy, 3 for residual lesion and 2 for recurrence at follow-up visits. The patient with squamous cell carcinoma in situ was treated with 3 courses. Average follow up was 38 months with a range of 4 to 142 months. No clinically detectable lesion was seen in any patient at final follow up. Two patients experienced transient ocular adverse effects, including 1 patient with mild keratopathy and another with chemosis. Conclusions: The use of 5% 5-FU has been described in the treatment of noninvasive squamous neoplasia. This article describes the authors experience with lesions involving the eyelid, including the eyelid margin. Expected dermatologic inflammation occurred following treatment regimens, and mild transient ocular adverse effects were seen in 2 patients. Topical 5-FU may be useful in the treatment of periocular actinic keratoses and squamous cell carcinoma in situ.