Since 1993 sulphadoxine/pyrimethamine (SP) has been used as the first-line drug for uncomplicated Plasmodium falciparum malaria in Malawi. To investigate the current efficacy of SP and other antimalarial drug resistance, we studied in vivo and in vitro responses to SP, chloroquine (CQ), mefloquine (MF), quinine (QN), and halofantrine (HF) in Salima, central Malawi. In a follow-up of 14 days, nine (13.8%) of 65 children under five showed RII/RIII parasitological resistance, and in in vitro microtests 18 (62.1%) of 29 isolates showed < 90% inhibition of schizont maturation at pyrimethamine 75 nmol/l blood medium mixture, indicating resistance. The discrepancy between in vivo and in vitro results might be partially explained by acquired immunity in this holoendemic area. In vitro one (3.4%) of 29 isolates failed schizont inhibition at 1.6 micromol/l blood of CQ, indicating resistance. Compared with an in vitro study conducted in 1988 in another region of Malawi using the same cut-off point, the proportion of resistant isolates had decreased significantly (P < 0.01). Although 31% of isolates were borderline, showing schizont maturation at 0.8 micromol/l blood but no schizonts at 1.6 micromol/l in our study, the results suggest possible recovery of CQ sensitivity after long-term absence of drug pressure. Resistance remains a major problem in malaria control. Monitoring resistance patterns in vitro provides early warning signs of impending loss of therapeutic efficacy of the standard treatment, and may detect changing patterns in alternative drug resistance.