Diclofenac 3% gel is an effective treatment for actinic keratoses (AKs) and is reported to be generally well tolerated with only mild local reactions. However, there is a subset of patients that seem to be susceptible to developing severe local reactions following application of diclofenac 3% gel. Although some of these reactions can be explained as being allergic contact dermatitis and/or photoallergic contact dermatitis, others cannot. We report a series of 10 patients who all developed severe local reactions following application of diclofenac 3% gel, despite negative diclofenac patch testing. This raises the question as to whether there is a subset of patients with skin cancer or AK lesions that are highly/more susceptible to local reactions caused by cyclo-oxygenase-2 (COX-2) inhibitors and peroxisome proliferator-activated receptor (PPAR) agonists? We speculate that underlying molecular differences exist in these patients that make the skin more susceptible to COX-2 inhibitors.