We evaluated cerebrospinal fluid amyloid-β 1-40 (Aβ40), amyloid-β 1-42 (Aβ42), total and phosphorylated-tau (t-tau and p-tau) in patients with symptomatic isolated cortical supratentorial superficial siderosis (SS), by prospectively recruiting ten patients with SS in the absence of pre-existing cognitive dysfunction, and comparing biomarkers with lobar hematoma cerebral amyloid angiopathy patients (LH-CAA, n = 13), Alzheimer's disease patients (AD, n = 42), and controls (n = 16). Compared to controls, SS patients showed statistically significant higher t-tau (p = 0.019) and lower Aβ42 (p = 0.0084). Compared to other groups, SS showed statistically significant lower t-tau, p-tau, and Aβ40 compared to AD (p = 0.0063, p = 0.0004, and p = 0022, respectively), and higher p-tau compared to LH-CAA (p = 0.012).