Gastroesophageal reflux disease (GERD), is a common disorder. The most effective medical treatment for GERD is a proton pump inhibitor (PPI). The aim of this study was to specify the most inexpensive PPI therapy for GERD, and to examine the implications of varying outcome measure, holding time, on the conclusions about the cost-effectiveness of the treatments. Proton pump inhibitors that have holding time of intragastric pH>4 for at least 11h in 24h period (esomeprazole, lansoprazole, omeprazole and rabeprazole), were included. In this cost-minimization analysis (CMA), data on holding times were gathered from scientific publications listed in MEDLINE, prices of proton pump inhibitors from the Finnish database of drug prices and the treatment dosages were taken from the official guide of drug therapies in Finland. A decision tree was applied and the probabilities utilized were acquired from three expert physicians. The cost-minimization analysis was performed in three settings. At first, drugs that had a holding time (pH>4) of 11h or more were included. Secondly, drugs that had a holding time of 12h or more were included, and thirdly, a holding time of 13h or more was required. In the first analysis, the least expensive PPI treatment was lansoprazole (average cost of 138.89 per patient). In the second analysis, least expensive treatment was rabeprazole (193.81 per patient), and in the third, rabeprazole again (193.81 per patient). Esomeprazole and omeprazole were not among two of the least expensive alternatives in any of the settings. Which proton pump therapy turns out to be the least expensive for GERD, depends on the length of the holding time desired. Varying the holding time of the drug had a profound effect on the conclusions about the cost-effectiveness of the alternative treatments.