Following a study showing an association between Ascaris and protection from cerebral malaria, we hypothesized helminths may have induced protection through immunoglobulin E (IgE) and the CD23/NO pathway. We compared the prevalence of helminth infections in 67 cerebral malaria patients and 217 hyperparasitemic controls with no complications. For 24 cerebral malaria cases and 56 controls, we compared reactive nitrogen intermediates (RNI) concentrations and their correlations to total IgE and sCD23 concentrations in helminth-infected and noninfected patients. We observed a dose-dependent association between helminth infections and protection from cerebral malaria (adjusted odds ratio [OR] = 0.36, 95% CI = 0.19-0.7, P = 0.002, linear trend P = 0.0007). Helminth-infected controls had higher RNI concentrations than those without helminths: 72 OD +/- 19 SD and 57 OD +/- 20 SD, respectively (P = 0.006). Logistic regression, including interaction terms between RNI and sCD23, showed that an increase of RNI could be both protective and pathogenic depending on the concentration of sCD23. Helminths increasing both the CD23 receptor and its ligand may have a role in the establishment of malaria tolerance through the CD23/NO pathway.