Background Omeprazole, a proton pump inhibitor (PPI), is widely used for the treatment of dyspepsia, peptic ulcer, gastroesophageal reflux disease, and functional dyspepsia. Polypharmacy is common in patients receiving omeprazole. Drug toxicity and treatment failure resulting from inappropriate combination therapy with omeprazole have been reported sporadically. Systematic review has not been available to address the pharmacokinetic drug-drug interaction (DDI) profile of omeprazole with adverse consequences, the factors determining the degree of DDI between omeprazole and comedication, and the corresponding clinical risk management. Methods Literature was identified by performing a PubMed search covering the period from January 1988 to March 2013. The full text of each article was critically reviewed, and data interpretation was performed. Results Omeprazole has actual adverse influences on the pharmacokinetics of medications such as diazepam, carbamazepine, clozapine, indinavir, nelfinavir, atazanavir, rilpivirine, methotrexate, tacrolimus, mycophenolate mofetil, clopidogrel, digoxin, itraconazole, posaconazole, and oral iron supplementation. Meanwhile, low efficacy of omeprazole treatment would be anticipated, as omeprazole elimination could be significantly induced by comedicated efavirenz and herb medicines such as St John’s wort, Ginkgo biloba, and yin zhi huang. The mechanism for DDI involves induction or inhibition of cytochrome P450, inhibition of P-glycoprotein or breast cancer resistance protein-mediated drug transport, and inhibition of oral absorption by gastric acid suppression. Sometimes, DDIs of omeprazole do not exhibit a PPI class effect. Other suitable PPIs or histamine 2 antagonists may be therapeutic alternatives that can be used to avoid adverse consequences. The degree of DDIs associated with omeprazole and clinical outcomes depend on factors such as genotype status of CYP2C19 and CYP1A2, ethnicity, dose and treatment course of precipitant omeprazole, pharmaceutical formulation of object drug (eg, mycophenolate mofetil versus enteric-coated mycophenolate sodium), other concomitant medication (eg, omeprazole-indinavir versus omeprazole–indinavir–ritonavir), and administration schedule (eg, intensified dosing of mycophenolate mofetil versus standard dosing). Conclusion Despite the fact that omeprazole is one of the most widely prescribed drugs internationally, clinical professionals should enhance clinical risk management on adverse DDIs associated with omeprazole and ensure safe combination use of omeprazole by rationally prescribing alternatives, checking the appropriateness of physician orders before dispensing, and performing therapeutic drug monitoring.