The effect of infertility on the psychological well-being of couples has been the subject of increasing attention in recent years. The frustration of couples of a relatively young age (ie, in their fourth decades) provokes not only anxiety and depression but also negative effects on the relationships. The objective of this study was to evaluate the effect of a diagnosis of male infertility on anxiety and depression in the men themselves and in fertile female spouses. The prospective cross-sectional study consisted of 264 participants, 72 males diagnosed with nonobstructive azoospermia (NOA) and their fertile spouses and 60 fertile couples attending our university between January 1, 2009, and April 30, 2010. The Beck Anxiety Inventory, Beck Depression Inventory (BDI), and hormone levels were measured during initial and follow-up visits. In NOA men, follicle-stimulating hormone and luteinizing hormone were positively associated with anxiety, in contrast to testosterone, which was inversely associated with anxiety. After the diagnosis of NOA, producing no testicular sperm, the panic intensity among men increased significantly, whereas their spouses exhibited less panic. By contrast, fertile female partners of NOA men reported higher BDI scores after the initial diagnosis of azoospermia, whereas their partners recorded higher levels of depression after the absence of testicular sperm was discovered. Insomnia was the most common complaint for both sexes after the diagnosis of azoospermia. Hormonal abnormalities had a negative effect on the quality of life. Physicians and clinicians should acknowledge the immense psychosocial effect of the diagnosis of male infertility on both males and their fertile female partners.