Background: The policy governing the treatment of malaria in Nigeria was changed in 2005 instituting the Artemisinin-Based Combination Therapies [ACTs] as first-line Drugs instead of Chloroquine due to rapidly developing resistance of Plasmodium falciparum. Methodology: The tolerability to [ACTs] was assessed in patients using a structured questionnaire and Visual analogue scale. These instruments were distributed systematically among the patients that presented with uncomplicated malaria after obtaining consent from the University of Benin Teaching Hospital, Benin City, Nigeria. Results: Among the five hundred and twenty patients that participated in the tolerability assessment of four different types of ACTs, male and female ratio was 1.3:1, Mean age 32.06 ± 2.3 years [Mean ± SD]. Artemether-Lumefantrine was the most frequently utilized and most tolerable. Two hundred and five [52.69%] respondents reported with forty-one different types of adverse effects of nine major systemic classes. Body weakness was the most frequent adverse effects reported in 112[54.63%] respondents. Adverse effects were significantly dependent on the type of ACTs used p<0.05; these were found to be most common with Artesunate-Mefloquine. Eleven patients were hospitalized due to very severe Body weakness and Dizziness. These severities were found common with Artesunate-Amodiaquine and Artesunate- Mefloqunie respectively. Despite the adverse effects, four hundred and seventy-six respondents (91.53%) were willing to repeat ACTs another time they have malaria. There were significant differences in symptomatic response on Days 0, 1, 2, 3, 7, 14 and 28 (p<0.05). 93% respondents felt extremely sick on Day 0, 68% had persistent fever on the third day of treatment and 71% had improved response after day 7. Conclusion: Anecdotal reports showed that ACTs have a modest tolerability, they are therefore recommended for patients that have uncomplicated malaria.