Background: There are few detailed etiologic studies of severe anemia in children from malaria-endemic areas and none inthose countries with holoendemic transmission of multiple Plasmodium species.Methodology/Principal Findings: We examined associates of severe anemia in 143 well-characterized Papua New Guinean(PNG) children aged 0.5–10 years with hemoglobin concentration ,50 g/L (median [inter-quartile range] 39 [33–44] g/L)and 120 matched healthy children (113 [107–119] g/L) in a case-control cross-sectional study. A range of sociodemographic,behavioural, anthropometric, clinical and laboratory (including genetic) variables were incorporated inmultivariate models with severe anemia as dependent variable. Consistent with a likely trophic effect of chloroquine oramodiaquine on parvovirus B19 (B19V) replication, B19V PCR/IgM positivity had the highest odds ratio (95% confidenceinterval) of 75.8 (15.4–526), followed by P. falciparum infection (19.4 (6.7–62.6)), vitamin A deficiency (13.5 (5.4–37.7)), bodymass index-for-age z-score ,2.0 (8.4 (2.7–27.0)) and incomplete vaccination (2.94 (1.3–7.2)). P. vivax infection was inverselyassociated (0.12 (0.02–0.47), reflecting early acquisition of immunity and/or a lack of reticulocytes for parasite invasion. Afterimputation of missing data, iron deficiency was a weak positive predictor (6.4% of population attributable risk).Conclusions/Significance: These data show that severe anemia is multifactorial in PNG children, strongly associated withunder-nutrition and certain common infections, and potentially preventable through vitamin A supplementation andimproved nutrition, completion of vaccination schedules, and intermittent preventive antimalarial treatment using nonchloroquine/amodiaquine-based regimens.