Noninfected erythrocytes form rosettes around those infected with trophozoites and schizonts of Plasmodium falciparum in vitro. These rosettes are thought to contribute to the microvascular obstruction which underlies the pathophysiology of severe falciparum malaria. To determine whether the percentage of infected erythrocytes forming rosettes for a parasite isolates in vitro correlates with the in vivo severity of disease, we studied the rosette formation behavior of 35 isolates of P. falciparum from patients with uncomplicated, severe, and cerebral malaria. There was a wide variation in the degree of rosette formation (0 to 53%). Four parasite isolates formed rosettes well (30 to 53%), and seven isolates formed rosettes poorly or not at all (0 to 5%), while the majority of the isolates formed rosettes to various degrees between these two extremes. In this relatively small sample of patients, we were unable to demonstrate a significant association between in vitro rosette formation and patients with cerebral malaria or conscious patients with significant renal (serum creatinine greater than 200 mumol/liter) or hepatic dysfunction (serum bilirubin greater than 50 mumol/liter and aspartate aminotransferase greater than 50 Reitman-Frankel units). However, there was an inverse relationship between rosette formation and cytoadherence (r = -0.575, P less than 0.01) which could not be explained on the basis of steric hindrance. This finding suggests that cytoadherence and rosette formation properties are intrinsic to the parasites, with isolates having a greater propensity for one or the other but not both. Further studies are required to establish the occurrence and pathophysiological role of rosette formation in vivo.