Malaria /HIV co-infection is a major challenge to public health in developing countries and yet potential drug-drug interactions between antimalarial and antiviral regimens have not been adequately investigated in people with both HIV and Plasmodium falciparum infections. Earlier studies on the use of artemether-lumefantrine (AL) in Nigeria have neither addressed its use in HIV-positive subjects nor in asymptomatic-malaria infection. The present study investigated associations between drug resistant P. falciparum and the use of medication for HIV management, drug-drug interactions between artemether-lumefantrine and antiretroviral drugs (ARV) and the molecular markers of artemether-lumefantrine and other antimalarial drugs. Results of the study revealed an elevated day 7 lumefantrine concentrations in HIV subjects on nevirapine treatment compared to their HIV-negative counterparts. Associations between elevated day 7 levels of lumefantrine and the persistent parasitaemia could not be evaluated due to inadequate power. Genetic analysis by DNA sequence of P. falciparum isolates revealed strong selection for the pfmdr1codon86N allele among all treated individuals. This polymorphism is a strong indicator of AL treatment failure or slow clearance in vivo. There was a 72.6% prevalence of the pfcrt76T mutations in the population and this was observed to be higher in the HIV-positive subjects. Three new mutations F73S, S97L and G165R were detected on the pfmdr1 gene and the first case S436F mutation on the pfdhps gene to be reported in Nigeria. The dhpsK540E and dhfrI164L mutations, associated with high-level resistance to sulfadoxine-pyrimethamine (SP) were not observed in our small sample size. The study also revealed that HIV-positive subjects were more likely to harbour parasites, at a higher density, before and after treatment. Improvement of the immune status of HIV-infected patients was suggested by the increase of CD4 cell count level in about 68% of the HIV-positive patients. This is a preliminary study and first of its kind to investigate drug-drug interactions between ARVs and the antimalarial drug AL in HIV-positive patients co-infected with P. falciparum in relation to parasite clearance. The findings of the study are very important but more work is urgently needed with a larger sample size to confirm these findings.