Measurement of the patients’ subjective experience of side‐effects of immunosuppressants is a critical post‐transplant outcome. This study aimed to update and validate the 45‐item Modified Transplant Symptom Occurrence and Symptom Distress Scale (MTSOSD) for novel immunosuppressive regimens. We used four steps: (1) literature review to identify immunosuppressant‐related symptoms; (2) screening of adverse event forms; (3) international experts’ evaluation of the appropriateness of each symptom; and (4) a pilot study in 24 renal transplant patients to test the clarity of instructions and items, and a pilot study in 84 lung transplant patients, to determine content and discriminant validity. Steps 1 and 2 produced a list of 76 symptoms. Clinical experts deemed 59 symptoms as being relevant for assessing symptom experience (step 3). Based on the first pilot testing, items and instructions were adapted to improve clarity. The second pilot testing showed that the updated MTSOSD‐59R was easy to complete, that items and instructions were understandable, and that symptom profiles differed between males and females, and between depressed and nondepressed patients (step 4). The MTSOSD‐59R is an instrument with established content and discriminant validity for assessing transplant patients’ symptom experience of side‐effects stemming from currently available immunosuppressive regimens.