BACKGROUND: Both helminth and malaria infections result in a highly polarized immune response characterized by IgE production. This study aimed to investigate the total serum IgE profile in vivo as a measure of Th2 immune response in malaria patients with and without helminth co-infection. METHODS: A cross sectional observational study composed of microscopically confirmed malaria positive (N = 197) and malaria negative (N = 216) apparently healthy controls with and without helminth infection was conducted at Wondo Genet Health Center, Southern Ethiopia. A pre-designed structured format was utilized to collect socio-demographic and clinical data of the subjects. Detection and quantification of helminths, malaria parasites and determination of serum IgE levels were carried out following standard procedures. RESULTS: Irrespective of helminth infection, individuals infected by malaria showed significantly high levels of serum IgE compared with malaria free apparently healthy controls (with and without helminth infections). Moreover, malaria patients co-infected with intestinal helminths showed high level of serum IgE compared with those malaria patients without intestinal helminths (2198 IU/ml versus1668 IU/ml). A strong statistically significant association was observed between malaria parasite density and elevated serum IgE levels (2047 IU/ml versus 1778 IU/ml; P = 0.001) with high and low parasitaemia (parasite density >50,000 parasite/mul of blood), respectively. Likewise, helminth egg loads are significantly associated with elevated serum IgE levels (P = 0.003). CONCLUSIONS: The elevated serum IgE response in malaria patients irrespective of helminth infection and its correlation with malaria parasite density and helminth egg intensity support that malaria infection is also a strong driver of IgE production as compared to helminths.