The main purpose of this study is to present objective data on the differences in anthropometrics and fitness variables between adult athletes and non-athletes with Down Syndrome (DS) members of the “Down Cordoba Association” (DCA), after adjusting for confounders. Twenty-seven adults, 7 athletes and 20 non-athletes with DS, participated in this study. Health-related fitness variables were measured with tests validated for this population. First, the characteristics of the subjects according to sex and sports practice are presented. Athletes present significantly higher values for height (p = 0.010) and waist-to-hip ratio (p = 0.005). Furthermore, male athletes compared to male non-athletes have lower values in % of body fat (p = 0.030), and in waist (p = 0.031) and hip (p = 0.041) circumferences. Furthermore, athletes have better values in tests of strength, cardiovascular endurance (66.60 ± 47.66 vs. 32.31 ± 24.49 (s); p = 0.037), and agility, but not in flexibility. Significant differences were only found in cardiovascular endurance. As a conclusion, the practice of sports among the users of the “Down Córdoba Association” in general leads to better health-related fitness values. Therefore, we encourage the guardians of people with DS in this association to motivate them to practice sports because this practice will more likely improve their overall health.