OBJECTIVE Proton pump inhibitors (PPIs) are the mainstay of current medical management for laryngopharyngeal reflux, and treatment often involves long-term use of this class of medications. The long-term adverse effects of PPI use have not been studied extensively, but several analyses have demonstrated epidemiological links between PPI use and adverse outcomes. These include altered mineral and vitamin absorption, orthopedic injury, acute coronary syndromes (ACS), and infectious risks. METHODS A PubMed search was performed for subject headings, including PPIs and adverse outcomes. Relevant studies were included in this review. Studies were compiled, reviewed, and compared in a narrative form. RESULTS Several epidemiological links between PPI use and metabolic, infectious, cardiac, and orthopedic adverse outcomes were found. No definite causal effects were identified. CONCLUSIONS Given these epidemiological patterns, we recommend that the clinician be aware of these possible unintended consequences. In addition, we recommend consideration of dual-energy X-ray absorptiometry (DEXA) bone density scans in at-risk patients who have not been previously tested. We recommend consideration of vitamin B₁₂ and iron levels in selected patients who are at high risk. We also recommend close communication with our cardiology colleagues, as we attempt to ascertain the relationship between clopidogrel and PPI use. We recommend caution in the use of omeprazole in patients undergoing active treatment for ACS. Finally, we recommend consideration of Helicobacter pylori or serum gastrin level testing in patients with known risk factors for gastric carcinoma.