Objective To evaluate the prevalence, and clinical and seminal impact of comorbidities in white European men presenting for couple infertility. Design Cross-sectional study. Setting Academic reproductive medicine outpatient clinic. Patient(s) Cohort of 2,100 consecutive infertile men (noninterracial infertile couples). Intervention(s) Obtaining complete demographic, clinical, and laboratory data from 2,100 consecutive infertile men with health-significant comorbidities scored via the Charlson comorbidity index (CCI; categorized 0 vs. 1 vs. ≥2) and semen analysis values assessed based on 2010 World Health Organization reference criteria. Main Outcome Measure(s) Assessment of the rate of comorbidities by means of CCI scores and possible associations between CCI, semen and hormonal parameters. Result(s) Descriptive statistics and regression models tested the associations among semen parameters, clinical characteristics, and CCI. When assessing general comorbidity prevalence, CCI 0, CCI 1, and CCI ≥2 was found in 1,921 (91.5%), 102 (4.9%), and 77 (3.6%) patients, respectively. Patient age and follicle-stimulating hormone levels increased as the general health status decreased. Conversely, the total testosterone levels and sperm concentration decreased as CCI scores increased. A higher rate of oligozoospermia and nonobstructive azoospermia was observed in patients with CCI ≥1. No differences were observed among the considered comorbidity groups in terms of testicular volume or further hormonal or seminal parameters. Both continuously coded and categorized sperm concentrations were independent predictors of CCI ≥1. Patients with sperm concentration <45.6 million/mL (most informative cutoff value) had a 2.74-fold increased risk of having a CCI ≥1. Conclusion(s) Decreased general health status appears to be associated with impaired male reproductive health, including lower sperm concentration, lower total testosterone levels, and higher follicle-stimulating hormone values.