Background: Off-label drug use may provide unwanted drug reactions (ADRs) or the absence of therapeutic effects due to a lack of clinical data. Prevalence of off-label drug use is rarest in the nephrology, rheumatology, and immunology divisions (11%) according to Radley et al (2006) with very few available references, further research is needed given the number of cases of nephrology, rheumatology, and immunology patients who entered into the top 10 cases of inpatient diseases in prof. Dr. Margono Soekarjo General Hospital. Method: This study aims to observe the use of off-label drugs in Patients with Deep Diseases in Prof. Dr. Margono Soekarjo General Hospital from January to March 2020. The data is taken prospectively with the method of total sampling, follow-up of clinical outcome development in patients, and determination of EBM using grade method. Out of a population of 878 patients were found to be the subject of 30 studies. Result: off-label drug use in the Nephrology Division (83.33%) includes folic acid, sodium bicarbonate, and CaCOa while in the Rheumatology Division (16.67%) using cyclosporine with therapeutic outcomes throughout patients with off-label drug use showed significant improvements to the decrease in the progressiveness of the patient's disease. Meanwhile, an evidence-based off-label treatment used in this study is recommended (level 1 EBM).