Doubts have been raised concerning the therapeutic efficacy of sulfadoxine-pyrimethamine due to poor clinical response necessitating the need for continuous monitoring and further advocating for the replacement of sulfadoxine-pyrimethamine with suitable alternatives. Statins are known to down regulate biosynthesis of dolichol and isoprenoid pyrophosphate, inhibiting in vitro growth of Plasmodium falciparum. This study was aimed at evaluating the clinical response of simvastatin plus sulfadoxine-pyrimethamine combination as compared to sulfadoxine-pyrimethamine alone in the chemotherapy of malaria. Malaria patients (n=60) confirmed by thick blood film and immunological tests were selected and informed written consent obtained. Patients were categorized into simvastatin plus sulfadoxine-pyrimethamine (test) and sulfadoxine-pyrimethamine alone (control). The University of Nigeria Teaching Hospital Research Ethics Committee reviewed the proposal and provided ethical clearance certification (NHREC/05/01/2008B). The WHO was adopted in the assessment of clinical response and patients followed up on days D0, D3, D7, D14 and D28 post-treatment. The analysis of data was done using GraphPad Prism 4.0 and data presented in tabular and graphical forms. The mean early treatment failure given as 9.2±0.26% in the test group was significantly decreased relative to 20.5±0.26% in the control; whereas mean late treatment failure given as 10.3±0.15% in the test group was reported relative to 23.6±0.22% in the control. There was statistically significant increase in adequate clinical and parasitological response given as 77.5±0.59% in the test group relative to 55.9±0.49% in the control. The mean parasite clearance time and fever clearance time given in the test group as 4.4±0.2 days and 55.3±2.6 hours were significantly reduced relative to 9.8±0.2 days and 87.4±4.5 hours recorded in the control. The clinical clearance rate given as 82.3±0.8% was significantly increased in the test group relative to 60±1.3% recorded in controls. A statistically significant decrease was recorded in the recrudescence rate given as 19.1±0.14% in the test group relative to 39±0.22% recorded in the control. The enhancement in clinical response in this study is attributable to modulating influence of statin treatment. Thus, the 3-HMG-CoA reductase inhibitor, simvastatin, is a potential candidate for combinational anti-malarial chemotherapy