Topical imiquimod and tumor necrosis factor (TNF)-alpha inhibitors have gained wide acceptance as safe and effective treatments for non-melanoma skin cancer (NMSC) and moderate to severe psoriasis, respectively. While mild to moderate application site reactions (ASRs) are a well-known and common phenomenon associated with imiquimod, the potential of TNF-alpha blockers to elicit cutaneous inflammatory reactions has only recently been recognized. We present two cases of severe, atypical ASRs which occurred during NMSC treatment with imiquimod in the context of infliximab administration for psoriasis, and consider the grounds supporting a non-fortuitous association. To date, no relation has ever been suggested between TNF-alpha inhibitors and increased susceptibility to developing exaggerated ASRs with imiquimod. We believe that this subject deserves further analysis; meanwhile, increased attention should be drawn to the possibility of this adverse interaction, as simultaneous treatment with TNF-alpha blockers and imiquimod is becoming increasingly frequent in daily practice.