The present part II review highlights pharmacokinetic drug-drug interactions (excluding those of minor severity) of medications used in prophylactic treatment of the main primary headaches (migraine, tension-type and cluster headache). The principles of pharmacokinetics and metabolism, and the interactions of medications for acute treatment are examined in part I. The overall goal of this series of two reviews is to increase the awareness of physicians, primary care providers and specialists regarding pharmacokinetic drug-drug interactions (DDIs) of headache medications. The aim of prophylactic treatment is to reduce the frequency of headache attacks using beta-blockers, calcium-channel blockers, antidepressants, antiepileptics, lithium, serotonin antagonists, corticosteroids and muscle relaxants, which must be taken daily for long periods. During treatment the patient often continues to take symptomatic drugs for the attack, and may need other medications for associated or new-onset illnesses. DDIs can, therefore, occur. As a whole, DDIs of clinical relevance concerning prophylactic drugs are a limited number. Their effects can be prevented by starting the treatment with low dosages, which should be gradually increased depending on response and side effects, while frequently monitoring the patient and plasma levels of other possible coadministered drugs with a narrow therapeutic range. Most headache medications are substrates of CYP2D6 (e.g., beta-blockers, antidepressants) or CYP3A4 (e.g., calcium-channel blockers, selective serotonin re-uptake inhibitors, corticosteroids). The inducers and, especially, the inhibitors of these isoenzymes should be carefully coadministered.