With respect to the high cost and limited availability of albumin, its use must be restricted to indications strongly supported by solid scientific evidence. It was anticipated that with the implementation of the National Health Reform Plan (NHRP), the consumption of albumin would increase as the result of decreasing patients' out-of-pocket costs. This study aimed to evaluate the efficacy of protocol implementation on the rationalization of albumin use in surgery wards of Cancer Institute of Imam Khomeini Hospital Complex, Tehran, Iran. Methods: This pre-post interventional study was conducted in 32-month phases from January to November 2014 in an Iranian University hospital. The first phase was before the implementation of NHRP, the second phase was after NHRP, and the last one was after the intervention. The first and second phases were conducted retrospectively. Data extraction was performed by a hospital pharmacist. During the third phase, the physicians were mandated to adhere to a local albumin protocol which had been prepared by clinical pharmacy service and approved by drug and therapeutic committee. Appropriateness of prescriptions regarding indication, dose, and duration based on local guideline was compared among groups. Findings: Although hospital bed-days of care remained consistent among phases, albumin was prescribed for 40, 45, and 8 patients during first, second, and third phases, respectively. This shows about 80% reduction of drug prescriptions in the last phase. The mean duration/dose of albumin in inappropriate indications reduced significantly from 11.3 ± 8.2 days/24.7 ± 21.2 vials in the second phase to 2.6 ± 1.7 days/5.6 ± 3.5 vials in the third phase, respectively (P = 0.001 and P = 0.003). Conclusion: Interactive collaboration through guideline implementation seems effective in rationalizing the use of high-cost medications such as albumin.