Headache is one of the most common reasons for patients to visit their general practitioner. Most of these patients suffer from migraine, tension-type headache, or a combination of the two; they tend to self-medicate using over the counter combination headache preparations, particularly acetylsalicyclic acid (ASA) and acetaminophen coformulated with caffeine, which is one of the most commonly used combination analgesics in these patients worldwide. We reviewed studies on the efficacy and safety of this combination. In the treatment of migraine and tension-type headache, the combination of ASA, acetaminophen, and caffeine has been shown to be more efficacious and superior to monotherapy with the single substances of the combination. According to literature, there is no evidence for higher prevalence of undesirable side-effects of combination analgesics in comparison to monotherapy.