We used the WHO in vivo seven day test, extended to 14 day follow up to evaluate the efficacy of the alternative antimalarial drugs in Nigeria (1992), where chloroquine resistant P. falciparum (CRPD) has been confirmed. One thousand and four patients were screened. Those fulfilling recruitment criteria were randomly treated with chloroquine (CQ), n = 50, halofantrine (H), n = 53, pyrimethamine-sulfadoxine (P-S), n = 52 and qinghaosu (Q), n = 53. Parasitological treatment failures were found with all drugs i.e. CQ-53.6pc, H-9.5pc, P-S-28.5pc and Q-2.0pc. H and Q were significantly more efficacious than CQ and P-S, p < 0.003 and p < 0.006, respectively. similarly symptom clearance after 48 hours by H and Q, was 76.3pc and 94pc respectively, better than CQ. P-S was not significantly better than CQ, 64.4pc and 63.3pc, respectively, p > 0.05. The symptom clearance rate of CQ has markedly reduced from 97.7pc to 67.7pc, and in increased proportion of RIII, from 5.9pc to 14.3pc, are signs of increase in chloroquine resistant Plasmodium falciparum. Drug resistant P. falciparum in Nigeria constitutes a serious problem to malaria chemotherapy.