High-density lipoprotein (HDL) cholesterol has been hypothesised to be a reliable marker of frailty and poor prognosis among the oldest elderly. We evaluate the relationship of HDL-cholesterol with measures of physical performance, muscle strength, and functional status in older persons aged 80years or older. Data are from baseline evaluation of the ageing and longevity study in the Sirente geographic area (ilSIRENTE study) (n = 364). Physical performance was assessed using the physical performance battery score [short physical performance battery (SPPB)], which is based on three-timed tests: 4-m walking-speed, balance, and chair-stand tests. Muscle strength was measured by hand-grip strength. Analyses of covariance were performed to evaluate the relationship of different HDL-cholesterol levels with physical function. In the unadjusted analyses, physical function (as measured by the 4-m walking-speed, theSPPB score, the basic and instrumental activities of daily living scales scores), but not hand-grip strength, improved significantly as HDL-cholesterol tertiles increased. After adjustment for potential confounders, which included age, gender, living alone, alcohol abuse, physical activity, congestive heart failure, diabetes, cerebrovascular diseases, osteoarthritis, albumin, urea, C-reactive protein and LDL cholesterol, the association of HDL-cholesterol tertiles with the 4-m walking-speed and the SPPB score was still consistent. The present study suggests that among very old subjects living in the community the higher levels of HDL-cholesterol are associated with better functional performance.