Reports of deteriorating quinine efficacy prompted us to investigate the ability of quinine-tetracycline to clear parasites and fever from patients with multiple drug-resistant Plasmodium falciparum infections. Past and present treatment results were compared at two study sites along the Thai-Cambodian border. In northeastern Thailand, quinine-tetracycline cleared parasites more quickly in 1990 than in 1987 (mean 3.4 and 4.0 days, respectively; P = 0.006). In southeastern Thailand, there were no significant differences between 1990 (n = 26) and 1981–1983 (n = 42) in the time taken to clear either parasites (median 96 and 93 hr, respectively; P = 0.35) or fever (mean 74 and 66 hr, respectively; P = 0.30). In vitro drug sensitivity testing revealed a two-fold decrease in susceptibility to quinine between 1983 and 1990 in isolates from the southeastern Thai-Cambodian border (mean inhibitory concentration 166 ng/ml and 320 ng/ml, respectively; P < 0.001). We conclude that oral quinine-tetracycline continues to reliably clear parasites and fever from falciparum malaria patients infected in eastern Thailand. Periodic re-evaluations are warranted, however, since the decrease in in vitro susceptibility to quinine may be followed by an in vivo decay in the treatment response.