Results from recent trials and advances in the fields of medicine and technology have altered the spectrum of indications for use of therapeutic plasma exchange. In this article we analyze changes in indications for therapeutic plasma exchange that have occurred during 27 years in Croatia. We retrospectively analyzed the database of the Department of Dialysis at the University Hospital Center, Zagreb (678 patients; 6596 procedures), for changes in indications for therapeutic plasma exchange from 1982 to 2008. The number of patients and procedures increased several-fold during the follow-up period, but the mean number of procedures per patient per year did not change significantly. Neurological disorders constituted the largest group of indications for therapeutic plasma exchange (66% of all indications), followed by hematological (16%), nephrological (6%), and rheumatological disorders (6%). Myasthenia gravis was the most frequent indication during the entire follow-up period, but the pattern of other indications changed, with the most frequent at the beginning of follow-up becoming the least frequent at the end of follow-up. The five most frequent indications represented 62.2% of all indications at the beginning of follow-up, whereas during the 1990s, this percentage increased to more than 90% of all indications. Since the year 2000, the spectrum of indications has grown, and the percentage of the five most common indications decreased to 79.9%. Despite changes in indications for therapeutic plasma exchange, this procedure is still applicable in various medical fields, either traditional or newly created with the development of medicine and technology.