Clinical pharmacy services are vital in the prevention of adverse drug events (ADEs) in clinical practice, extending beyond the hospital to chronic disease management in outpatient settings. This study sought to evaluate the cost benefit of a clinical pharmacy intervention in resolving treatment-related problems (TRPs) among hospital outpatients with chronic diseases. From the hospital system perspective, the cost-benefit analysis was based on a randomized clinical trial in the general outpatients of the major hospital in Jordan. Eligible patients were randomly assigned to either an intervention or a control group. TRPs were identified in both study groups, but interventions were delivered only to the intervention group via a home medication management review (HMMR) by a clinical pharmacist. A follow-up in both groups took place 3months after recruitment. The total economic benefit was the sum of (a) cost savings due to intervention and (b) cost avoidance associated with preventable ADEs. The primary outcome measures were the net benefit and benefit-to-cost ratio with the clinical pharmacist-based HMMR. In both groups, 158 TRPs were identified, and 79 interventions were provided in the study group. The monthly cost of intervention was JD764 (US $1078), and the total monthly benefit was JD4570 (US $6444), leading to a benefit-to-cost ratio of 5.98 and an annual net benefit of JD45669 (US $64393). Sensitivity analyses confirmed the robustness of results. The RCT-based cost-benefit evaluation provided evidence-based insight into the economic benefit of a clinical pharmacist-provided HMMR for preventing ADEs in the general chronic diseases outpatients. This intervention method against the TRPs among outpatients is cost beneficial and offers substantial cost savings to the health care hospital payer in Jordan.