BACKGROUND: Uncommon and rare adverse events (AEs), with delayed onset may not be detected before new drugs are licensed and deployed. The present study examined the post licensure safety of dihydroartemisinin-piperaquine (DHP) as an additional treatment for malaria in Ghana. The relationship between the incidence of AEs, treatment completion rate, participant characteristics and concomitant medications are reported. METHODS: A study conducted from September 2013 to June 2014 in Navrongo, Kintampo and Dodowa health research centres in Ghana is presented. Participants had confirmed malaria and no known allergy to study drug. Patients provided informed consent and had their symptoms and results of their clinical examinations documented. Treatment with Eurartesim® (20/160mg dihydroartemisinin and 40/320mg piperaquine by Sigma-Tau Incorporated) was given, according to the body weight of patients. First treatment doses were under observation but the second and third doses were taken at home except in a sub-study involving a nested cohort. Patients were contacted at Day 5 (± 2 days) either on telephone or by a home visit to document any AEs experienced. Patients were asked to report to the study team any other AEs that occurred within 28 days post-treatment. All patients in the nested cohort had electrocardiogram (ECG). FINDINGS: A total of 4563 patients, 52.1% females and 48.2% <6 years completed the study. A total of 444 patients were enrolled into the nested cohort. About 33% had temperature ≥ 37.5°C at enrolment. Approximately 3.4% reported taking prior antimalarials, 19.4% other medications and 86% took at least one concomitant medication. Incidence of AEs was 7.6% including infections (4.6%), gastrointestinal disorders (1.0%) and local reactions at the site of venesection (0.5%). Others were respiratory disorders (0.4%) and nervous system disorders (0.3%). There were nine adverse events of special interest (AESI); itching/pruritus (7), dizziness (1), and skin lesions (1). Patients who took medications prior to enrolment had higher incidence of AEs compared with those without (9.3% vs. 6.1%; P<0.001). Statistically significant associations were found between the reported AEs and age of patients (P<0.001), their body mass index (BMI) (P< 0.001) and parasite densities (P< 0.001). CONCLUSION: Dihydroartemisinin-Piperaquine was well tolerated with no serious safety concerns identified. Obesity and prior enrolment medication were among significant factors associated with increased AEs reporting.