To search for evidence of a protective role of the CD23/NO pathway against cerebral malaria, concentrations of reactive nitrogen intermediates (RNI) and sCD21, total immunoglobulin (Ig)E and sCD23 were compared between 17 cases of cerebral malaria and 33 controls. The geometric mean of sCD23 concentration was higher among cerebral malaria cases than among controls (optical density 2643/1495, P = 0.01). The ratio between sCD21 and sCD23 was significantly lower in cerebral malaria cases than in controls (0.67 +/- 0.02 versus 0.77 +/- 0.02, respectively, P = 0.009). Multiple linear regression analysis showed that, among cerebral malaria cases, there was a clear correlation between RNI and both IgE (P = 0.007) and sCD21 (P < 0.0001). Among controls, there was a strong negative correlation between RNI and sCD23 concentrations (r = -0.61, P < 0.0001). However, multivariate analysis unmasked the fact that, in controls, there was also a positive correlation between RNI and IgE (P = 0.045). Logistic regression showed that increased RNI concentrations were associated with a cerebral malaria adjusted odds ratio of 1.05 per unit increase [95% confidence interval (CI) 1.006-1.1, P = 0.02] and that an increased ratio between sCD21 and sCD23 was associated with protection from cerebral malaria (adjusted OR = 0.00001 per unit increase (95% CI 0-0.03, P = 0.005). These different immunological profiles suggest that, among controls, the CD23/NO pathway was chronically stimulated whereas, in cerebral malaria, its stimulation was acute, which could explain why some patients developed cerebral malaria and others did not.