Endothelial activation and subclinical microvascular occlusions are an ongoing process during steady-state sickle cell disease, leading to interleukin production and an acute-phase response. Alpha-2-macroglobulin (α2M) is an acute-phase protein mainly regulated by interleukin-6 (IL-6). On the other hand, α2M acts as a carrier protein for IL-6 during inflammatory stress. The purpose of this study is to further assess the interactions between IL-6 and α2M as potent modulators of inflammatory reactions during the steady state of sickle cell disease. We measured α2M and IL-6 levels in 21 patients (12 male, 9 female; age range 12–44 years) in the steady state of sickle cell disease. Four patients had homozygous sickle cell anaemia and 17 had double heterozygous sickle cell/β-thalassaemia. Diagnostic quantification of α2M was performed by rate nephelometry. Commercial enzyme immunoassay test kits were used for the quantitative measurement of IL-6. The α2M and IL-6 levels were compared to the values obtained from healthy volunteers. Mean values (± SD) of α2M and IL-6 were found to be significantly increased (p < 0.0005) in the patients (α2M: 337.2 ± 104 mg/dl; IL-6: 4 ± 2.1 pg/ml) compared to the healthy controls (α2M: 204.2 ± 45.8 mg/dl; IL-6: 1.15 ± 2.5 pg/ml). IL-6 values were positively correlated with α2M levels (r = 0.61, p < 0.01). We observed increased α2M and IL-6 levels in steady-state sickle cell disease and a positive correlation between these two inflammatory mediators. We suggest that α2M is a potent modulator of the inflammatory reaction and tissue repair mechanism during steady-state microvascular occlusions. Elucidating the role of α2M in sickle cell disease could lead to the development of novel strategies and therapies for preventing the harmful systemic or local effects of excess cytokine production.