The effect of cardiac failure (CF) and comorbidity on disability in older persons was studied in a cross-sectional survey. The whole population aged 65 + years (n=652; 628 eligible) living in a small town near Florence (Italy) was enrolled. Finally, 459 individuals (73.0% of eligible) underwent a multidimensional evaluation. CF was defined as a NYHA II-IV class in the presence of an obviously abnormal ECG. Disability was assessed by the 14-item WHO scale. Comorbid conditions that had a prevalence >5% and might be considered pathophysiologically unrelated to CF were also identified. The univariate association of CF with disability was analyzed. Multivariate associations were estimated as well, by taking simultaneously into account the effect of comorbid conditions that had an independent effect on disability and were considered as either confounders or effect modifiers of that association. Prevalence of CF [6.1% in the whole study population) was higher with advancing age ( >or=75 years: 8.3 versus 65-74 years: 4.5%, odds ratio, OR: 1.93, 95% confidence interval, CI: 1.02-4.18), in the presence of hypertension (OR: 2.87, 95% CI: 1.32-6.23), and among individuals who were living alone (OR: 2.44, 95% CI: 1.10-5.56). CF was associated with a higher prevalence of disability (38.5 versus 19.5% OR 2.67, 95% CI: 1.21-5.92). Comorbidity modified the association of CF with disability following two patterns: while the independent effect of CF on the prevalence of disability was similar in the absence or in the presence of chronic obstructive pulmonary disease, hearing impairment, gastrointestinal tract disease, or osteoarthritis, such effect was much larger in the presence than in the absence of visual impairment, previous stroke, or urinary incontinence. The composite pathophysiological pathways of such different interactions are still to be elucidated.