Objective: To assess the distribution of ABO blood group and their relationship with Plasmodium falciparum (P. falciparum) malaria among febrile outpatients who sought medical attention at Dore Bafeno Health Center, Southern Ethiopia. Methods: A total of 269 febrile outpatients who visited Dore Bafeno Health Center, Southern Ethiopia, were examined for malaria and also tested for ABO blood groups in January 2010. The blood specimens were collected by finger pricking, stained with Geimsa, and examined microscopically. Positive cases of the parasitemia were counted. CareStartTM Malaria Pf/Pv Combo was also used to test the blood specimens for malaria. ABO blood groups were determined by agglutination test using ERYCLONE® antisera. Data on socio-demographic characteristics and treatment status of the participants were also collected. Chi-square and ANOVA tests were used to assess the difference between frequencies and means, respectively. Results: Out of a total of 269 participants, 178 (66.2%) febrile patients were found to be infected with Plasmodium parasites, among which 146 (54.3%), 28 (10.4%), and 4 (1.5%) belonged to P. falciparum, P. vivax, and mixed infections, respectively. All febrile patients were also tested for ABO blood groups and 51.3%, 23.5%, 21.9% and 3.3% were found to be blood types of O, A, B and AB, respectively. Both total malaria infection and P. falciparum infection showed significant association with blood types (P<0.05). The proportion of A or B but not O phenotypes was higher (P<0.05) in individuals with P. falciparum as compared with non-infected individuals. The chance of having P. falciparum infection in patients with blood groups A, B and AB was 2.5, 2.5 and 3.3 times more than individuals showing blood O phenotypes, respectively. The mean P. falciparum malaria parasitaemia for blood groups A, B, AB, and O were 3 744/μL, 1 805/μL, 5 331/μL, and 1 515/μL, respectively (P<0.01). Conclusions: The present findings indicate that individuals of blood groups A, B and AB are more susceptible to P. falciparum infection as compared with individuals of blood group O. Nevertheless, further in depth studies are required to clearly establish the role that ABO blood group plays in P. falciparum malaria.