Drug resistance has been shown to increase malaria mortality and morbidity in both community- and hospital-based studies. We investigated the association between two Plasmodium falciparum drug resistance-related molecular markers and clinical profiles of severe malaria in children hospitalised in Niger. PCR-RFLP analysis showed that the codon 108 mutation of the pfdhfr gene was positively linked to severe malarial anaemia. These findings are consistent with persistent parasite infection leading to unbalanced anaemia in young children. No significant relationship was found between the molecular markers and hypoglycaemia or hyperparasitaemia. Conversely, the pfcrt T76 mutation was found to be negatively associated with cerebral malaria and neurological symptoms, such as convulsions and coma. These results have implications for the strain-specific virulence hypothesis and for parasite fitness and evolution. Our findings are discussed in regard to the local malaria transmission level.