Background: Malaria is one of the main causes of mortality in tropical zone. Specific immune responses are induced by parasite, including the release of cytokines from peripheral blood mononuclear cells. Sickle cell trait confers a high degree of resistance to severe and complicated malaria. The present study aims to assess immunological response of P. falciparum infection by measuring of total IgG level and IL-6, IL-12 & IL-18 levels for P. falciparum among Saudi Arabian patients with and without sickle-cell trait. Patients and Methods: Thirty patients who had clinical suspicion of malaria and sickle-cell trait attending Jazan general hospital in KSA were included in the study. Malaria patients with sickle-cell trait will be matched with a control (thirty patients diagnosed to have malaria but without sickle-cell trait). Diagnosis of malaria was done by Immunochromatography strip and blood film. Diagnosis of Sickle-cell trait was done by hemoglobin electrophoresis assessment of total IgG titre and Interleukin 6, 12, 18 levels using ELIZA. Results: Cytokines and IgG in uncomplicated clinical malaria (n = 22) and severe malaria (n = 7) were IL6 (83.1 pg/mL) versus (75.2 pg/mL), IL12 (19.4 pg/mL) versus (16.3 pg/mL), IL18 (22.45 pg/mL) versus (24.2 pg/mL) and IgG (13.3 SD) versus (4.5 SD). Differences in the IL6, IL12 and IgG were statistically significant (p value >0.02, >0.004 & >0.002 respectively). Among malaria patients with sickle cell trait, Cytokines and IgG in asymptomatic (n = 19) and uncomplicated clinical malaria (n = 11) were IL6 (88.9 pg/mL) versus (79.2 pg/mL), IL12 (24 pg/mL) versus (22.9 pg/mL), IL18 (24.2 pg/mL) versus (31.2 pg/mL) and IgG (27 SD) versus (7.35 SD). Differences in IgG were statistically significant (p value ≥ 0.003). Serum IL6 levels were higher in patients with uncomplicated clinical malaria without sickle cell trait (median 83.1 ± 5.1 pg/mL) than in patients with uncomplicated clinical malaria with sickle cell trait (medians 79.2 ± 4.5 pg/mL). This difference was statisticall