It has been demonstrated that 40% of patients admitted to pulmonary medicine wards use proton pump inhibitors (PPIs) without a registered indication. To assess whether implementation of a guideline for proton pump inhibitor (PPI) prescription on pulmonary medicine wards could lead to a decrease in use and improved appropriateness of prescription. This prospective study comprised two periods, i.e. the situation before and after guideline implementation. In each period, 300 consecutive patients were included. We registered patient characteristics, medications and occurrence of upper gastrointestinal-related disorders. After implementation, fewer patients were started on PPIs [21% vs. 13%; odds ratio (OR): 0.56; 95% confidence interval (CI): 0.33-0.97] and more users discontinued their use; however, the latter was not significant (3% vs. 6%; OR for continuation: 0.56; 95% CI: 0.14-2.23). Multivariable logistic regression analysis confirmed that PPI use during hospitalization decreased after implementation (adjusted pooled OR: 0.54; 95% CI: 0.32-0.90). Implementation did not result in a change in reported reasons for PPI prescription. There was no significant difference in the occurrence of upper GI-related disorders in the first 3 months after discharge. Guideline implementation for PPI prescription on two pulmonary medicine wards resulted in a reduction in the number of patients starting PPIs during hospitalization, but appropriateness of prescribing PPIs was not affected. Further studies are needed to determine how appropriateness of PPI prescription on pulmonary medicine wards can be further improved.