OBJECTIVES: The objective of this study was to describe the pattern and trends of antibiotic resistance of Pseudomonas aeruginosa over a six-year period in a Saudi Arabian hospital. METHODS: This was a retrospective study of the antibiotic resistance of outpatient and inpatient isolates of P. aeruginosa. Only one isolate per patient per year was included in the study. RESULTS: During the study period a total of 2679 isolates of P. aeruginosa were available for analysis. Outpatient isolates constituted 48% of the total number, and of these 23.4% were obtained from wound cultures. For the inpatient isolates, 33.6% and 30% were obtained from the respiratory tract and wounds, respectively. There was no significant increase in the resistance rates of outpatient isolates to the tested antibiotics over time. On the other hand, inpatient isolates showed a statistically significant increase in resistance rates to piperacillin, ceftazidime, imipenem, and ciprofloxacin (p<0.001). Over the study period, the resistance rates of outpatient and inpatient isolates to piperacillin, ceftazidime, imipenem, and ciprofloxacin were 4.6% and 11.5%, 2.4% and 10%, 2.6% and 5.8%, and 3% and 6%, respectively. Gentamicin demonstrated the highest resistance among all tested aminoglycosides for outpatient isolates (6%) and inpatient isolates (6.7%). Resistance to more than two classes of antibiotics was present in 1-2% of inpatient isolates and in 0% of outpatient isolates. CONCLUSION: Antibiotic resistance continues to be a problem especially in inpatient isolates and is likely to be related to increased antibiotic use. Thus, continued monitoring of antibiotic resistance is of great importance to ensure the proper use of antibiotics and to detect any increasing trends in resistance.