BACKGROUND: In 2004, Ghana implemented the artemisinin-based combination therapy (ACT) policy. Health worker (HW) adherence to the national malaria guidelines on case-management with ACT for children below 5 years of age and older patients presenting at health facilities (HF) for primary illness consultations was evaluated 5 years post-ACT policy change. METHODS: Cross-sectional surveys were conducted from 2010 to 2011 at HFs that provide curative care as part of outpatient activities in two districts located in the middle belt of Ghana to coincide with the periods of low and high malaria transmission seasons. A review of patient medical records, HW interviews, HF inventories and finger-pricked blood obtained for independent malaria microscopy were used to assess HW practices on malaria case-management. RESULTS: Data from 130 HW interviews, 769 patient medical records at 20 HFs over 75 survey days were individually linked and evaluated. The majority of consultations were performed at health centres/clinics (68.3 %) by medical assistants (28.6 %) and nurse aids (23.5 %). About 68.4 % of HWs had received ACT-specific training and 51.9 %, supervisory visits in the preceding 6 months. Despite the availability of malaria diagnostic test at most HFs (94 %), only 39.8 % (241) out of 605 (78.7 %) patients who reported fever were investigated for malaria. Treatment with ACT in line with the guidelines was 66.7 %; higher in <5 children compared to patients ≥5 years old. Judged against reference microscopy, only 44.8 % (107/239) of ACT prescriptions that conformed to the guidelines were "truly malaria". Multivariate logistic regression analysis showed that HW were significantly more likely to comply with the guidelines if treatment were by low cadre of health staff, were for children below 5 years of age, and malaria test was performed. CONCLUSION: Although the majority of patients presenting with malaria received treatment according to the national malaria guidelines, there were widespread inappropriate treatment with ACT. Compliance with the guidelines on ACT use was low, 5 years post-ACT policy change. The Ghana NMCP needs to strengthen HW capacity on malaria case-management through regular training supported by effective laboratory quality control measures.