The risk factors associated with hyperparasitemia at presentation and after treatment with different antimalarial drug regimens were evaluated in 1,048 children enrolled prospectively in seven antimalarial drug trials between July 1996 and September 2003 in a hyperendemic area of southwestern Nigeria. The outcomes of treatment of hyperparasitaemia, and gametocyte carriage following treatment were also evaluated. The children were assigned to one of seven treatment groups: chloroquine (CQ) only; pyrimethamine-sulfadoxine (PS) only; amodiaquine (AQ) only; CQ plus chlorpheniramine (CQCP); PS combined with CQ or AQ (COM); PS combined with probenecid (PPS); and halofantrine (HF). Hyperparasitaemia was found in 100 (9.5%) of the 1,048 children at enrolment (day 0). Following oral therapy, 1.2% of all patients (i.e. 13 patients) became hyperparasitaemic, which developed in all patients by day 1 of follow-up. In a multiple regression model, age < or = 5 years, and a core temperature (oral or rectal) > or = 39.5 degrees C were found to be independent risk factors for hyperparasitaemia at enrolment. Following therapy, the cure rate on day 14 was significantly lower in those treated with CQ compared to other treatment groups. Severe resistance (RIII) response to treatment occurred significantly more frequently in those with hyperparasitaemia at enrolment than in those without, and was seen in five and one child with hyperparasitaemia who were treated with CQ and CQCP, respectively. Gametocyte carriage was insignificantly lower at enrolment and at all times following treatment in children with hyperparasitaemia than in age- and gender-matched children without hyperparasitaemia who received the same treatment. The results are discussed in the light of management of uncomplicated hyperparasitaemia in children in endemic settings.