Aim: to elucidate causes of primary refractoriness to phosphodiesterase type 5 inhibitors. Materials and methods: 28 men aged from 38 to 59 (mean 46) years suffering from erectile dysfunction and primary refractoriness to the treatment with phosphodiesterase type 5 inhibitors were interviewed using the International Index of Erectile Function (IIEF-5) questionnaire. In addition, they were examined by ultrasound dopplerography of penile vessels, subjected to neurologic testing and measurement of blood testosterone, TSH, prolactin, and glucose levels. Results and discussion: The primary refractoriness to the treatment with phosphodiesterase type 5 inhibitors was attributable to hypothyroidism in 3.5% of the cases, to diabetic neuropathy in 3.5%, to complications of radical prostatectomy in 3.5%, to hyperprolactinemia in 7%, to atherosclerosis of cavernous arteries in 7%, to venogenic erectile dysfunction in 7%, to hypogonadism in 11%, to combination of hypogonadism, diabetic neuropathy and angiopathy in 57%. Hypothyroidism, hyperprolactinemia, hypogonadism, and type 2 diabetes mellitus (12.5% of the cases) were detected for the first time in the examined patients. Pathogenetic therapy resulted in the elimination of erectile dysfunction in the patients presenting with hypothyroidism, hyperprolactinemia, and isolated hypogonadism. Combined treatment of erectile dysfunction with Nebido and Levitra proved efficacious in 14 of the 16 patients with combined hypogonadism, diabetic neuropathy, and angiopathy. Conclusion: The main causes of primary refractoriness to phosphodiesterase type 5 inhibitors appear to be endocrinopathies and diabetic neuro/angiopathy. Combined examination of the patients in these conditions makes it possible to reveal dangerous disorders. Self-treatment with phosphodiesterase type 5 inhibitors is undesirable. Medicamental therapy (including combined application of testosterone preparations and phosphodiesterase type 5 inhibitors) permits to cope with erectile dysfunction in 75% of the patients.