α-Thalassemia is one of the most important genetic modulators of sickle cell disease (SCD). Both beneficial and detrimental effects have been described previously. We use a 12-year data set on a large cohort of patients with HbSS (n = 411) and HbSC (n = 146) to examine a wide range of these clinical and laboratory associations. Our novel findings are that α-thalassemia strongly reduces erythrocyte potassium chloride co-transporter (KCC) activity in both HbSS and HbSC (p =.035 and p =.00045 respectively), suggesting a novel mechanism through which α-thalassemia induces a milder phenotype by reducing red cell cation loss. This may be particularly important in HbSC where reduction in mean cell hemoglobin concentration is not seen and where KCC activity has previously been found to correlate with disease severity. Additionally, we show that α-thalassemia not only increases hemoglobin in patients with HbSS (p =.0009) but also reduces erythropoietin values (p =.0005), demonstrating a measurable response to improved tissue oxygenation. We confirm the reno-protective effect of α-thalassemia in patients with HbSS, with reduced proteinuria (p =.003) and demonstrate a novel association with increased serum sodium (p =.0004) and reduced serum potassium values (p = 5.74 × 10−10). We found patients with α-thalassemia had a reduced annualized transfusion burden in both HbSS and HbSC, but α-thalassemia had no impact on annualized admission rates in either group. Finally, in a larger cohort, we report a median survival of 62 years in patients with HbSS (n = 899) and 80 years in those with HbSC (n = 240). α-thalassemia did not influence survival in HbSS, but a nonsignificant trend was seen in those with HbSC.