Background <p>Both autonomic dysfunction and frailty are common and complex geriatric syndromes with similar negative health outcomes. Both conditions are characterized by a loss of homeostasis that makes individuals more vulnerable to stressors.</p> Aim <p>The primary aim of this study is to examine the association between drugs that affect autonomic function and frailty onset in community-dwelling octogenarians. The secondary aim is to investigate the relationship between autonomic dysfunction and frailty onset in this population.</p> Methods <p>In total, 372 nonfrail adults aged 80 years and above (mean age 83 ± 3 years) from the BUTTERFLY project were prospectively followed for 2 years (mean follow-up of 22 ± 6 months). The association between autonomic dysfunction (defined as neurogenic orthostatic hypotension and symptoms of orthostatic hypotension), the use of medications affecting autonomic function, and frailty status were examined using binary logistic regression analysis.</p> Results <p>The completely adjusted binary logistic regression model showed that the use of drugs affecting autonomic function was associated with frailty {adjusted odds ratio (aOR) = 1.78 [95% confidence interval (CI) 1.06–3.00], <i>p</i> = 0.030}. Furthermore, symptoms of orthostatic hypotension were related to frailty (aOR = 2.98 [95% CI 1.13–7.88], <i>p</i> = 0.027).</p> Conclusions <p>Our results show that symptoms of orthostatic hypotension and the use of drugs that affect autonomic function are accompanied with respectively 3-fold and 1.8-fold higher odds of frailty onset in persons aged 80 years and over. Therefore, pharmacological treatment that affects autonomic function should be started with caution and timely discontinued in older persons.</p>