• Ability to start treatment within 1 week of enrollment
• Patients must be age ≥18, not of childbearing potential, and have the presence of 4-15 clinically, visibly confirmed and discrete AKs in an at least 25 cm2 contiguous area on the head, neck, arm, or hand.

Because no dosing or adverse event data are currently available on the use of fluorouracil in combination with calcipotriene in patients <18 years of age, children are excluded from this study.

• Patients with a prior or concurrent malignancy whose natural history or treatment does not interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
• The effects of topical fluorouracil and/or fluorouracil plus calcipotriene on the developing human fetus are unknown. From the topical fluorouracil package insert: "One birth defect (cleft lip and palate) has been reported in the newborn of a patient using EFUDEX as recommended. One birth defect (ventricular septal defect) and cases of miscarriage have been reported when EFUDEX was applied to mucous membrane areas. Multiple birth defects have been reported in a fetus of a patient treated with intravenous fluorouracil."11 For this reason, we are excluding women of child-bearing potential. This includes all female patients, between the onset of menses (as early as 8 years of age) and 55 years unless the patient presents with an applicable exclusionary factor which may be one of the following:

Postmenopausal (no menses in greater than or equal to 12 consecutive months). History of hysterectomy or bilateral salpingo-oophorectomy. Ovarian failure (Follicle Stimulating Hormone and Estradiol in menopausal range, who have received Whole Pelvic Radiation Therapy).

History of bilateral tubal ligation or another surgical sterilization procedure.

• Ability to understand and the willingness to sign a written informed consent document.

• Known allergy to any component of the medications or vehicle.
• A wound or suspected skin cancer within 5cm of the area to be treated
• Immunosuppression, or use in the past month of medications that could impede skin assessment including but not limited to:

Other topical medications with active ingredients including: topical steroids, topical calcineurin inhibitors, topical retinoids, imiquimod, diclofenac, etc.

Artificial tanners Cytotoxic medications including: systemic fluorouracil, bleomycin, doxorubicin, cisplatin, etc.

Ultraviolet therapy Oral nicotinamide Oral retinoids including: isotretinoin, acitretin

• History of hypercalcemia
• Clinical evidence of vitamin D toxicity
• The effects of topical fluorouracil and/or fluorouracil plus calcipotriene on the developing human fetus are unknown. From the topical fluorouracil package insert: "One birth defect (cleft lip and palate) has been reported in the newborn of a patient using EFUDEX as recommended. One birth defect (ventricular septal defect) and cases of miscarriage have been reported when EFUDEX was applied to mucous membrane areas. Multiple birth defects have been reported in a fetus of a patient treated with intravenous fluorouracil."11 For this reason, we are excluding women of child-bearing potential. This includes all female patients, between the onset of menses (as early as 8 years of age) and 55 years unless the patient presents with an applicable exclusionary factor which may be one of the following:

Postmenopausal (no menses in greater than or equal to 12 consecutive months). History of hysterectomy or bilateral salpingo-oophorectomy. Ovarian failure (Follicle Stimulating Hormone and Estradiol in menopausal range, who have received Whole Pelvic Radiation Therapy).

History of bilateral tubal ligation or another surgical sterilization procedure.