Although oral phosphodiesterase 5 inhibitors (PDE5-Is) are highly efficacious for many men with erectile dysfunction (ED), a relatively large subset of ED patients who do not respond to PDE5-Is has been identified. This review assessed the possible factors related to nonresponse to PDE5-Is in patients with ED. The review was based on previously published studies and involved a PubMed–MEDLINE search from January 1998 (year of sildenafil’s approval) through to January 2014. To achieve the maximum sensitivity of the search strategy and identify all studies, we combined ‘oral phosphodiesterase 5 inhibitors’ or ‘sildenafil’ or ‘vardenafil’ or ‘tadalafil’ as Medical Subject Headings (MeSH) terms or keywords with ‘non-response’ or ‘response’ or ‘failure’ or ‘erectile dysfunction’ or ‘etiologic factors’. Several factors are possibly related to nonresponse, including inadequate administration, instructions/inappropriate use, misdiagnosis, uncontrolled comorbidities, severe ED, psychosocial issues/personal-related factors, partner-related factors, and pharmacogenetic/pharmacogenomic factors. Real nonresponders mostly suffer from severe end-organ failure or pharmacogenetic factors, whereas correctable factors are seen as the cause in pseudononresponders. Awareness and early recognition of the etiological factors of nonresponse to PDE5-Is can help clinicians improve the treatment outcome.