Although symptoms are common and frequently severe in patients on maintenance hemodialysis, little is known about the relationship between cultural background and symptom burden. The aim of this study was to explore differences in the prevalence and severity of symptoms between American and Italian hemodialysis patients. We administered the 30-item Dialysis Symptom Index to American and Italian patients receiving maintenance hemodialysis during routine dialysis sessions. The prevalence and severity of individual symptoms were compared between patient populations, adjusting for multiple comparisons. Multivariable logistic regression and ordinal logistic regression were used to assess the independent associations of cultural background with the prevalence and severity of symptoms, respectively. We enrolled 75 American and 61 Italian patients. American patients were more likely to be black (36% vs. 0%, P<0.001) and diabetic (53% vs. 13%, P<0.001). Italian patients were more likely to report decreased interest in sex, decreased sexual arousal, feeling nervous, feeling irritable, and worrying (P<0.001, respectively). Adjustment for demographic and clinical variables had no impact on these cultural differences in symptom prevalence. The median severity of 11 symptoms including muscle soreness, muscle cramps, and itching was greater among Americans (P<0.001, respectively), although nearly all of these differences were rendered nonstatistically significant with adjustment for race, diabetes, and/or Kt/V. Italian patients receiving chronic hemodialysis report a greater burden of symptoms than American patients, particularly those related to sexual dysfunction and psychosocial distress. These findings suggest that cultural background may affect adaptation to chronic hemodialysis therapy.