Antimicrobial resistance in Pseudomonas aeruginosa is a serious clinical problem. To determine the incidence of multi-drug resistant P. aeruginosa, resistance rates of P. aeruginosa clinical isolates against commonly used antibiotics were evaluated for the period 1998 to 2002. Multi-drug resistance was defined as resistance to at least three of the four drugs, ceftazidime, imipenem, ciprofloxacin, and tobramycin. Resistance to most anti-pseudomonal agents has increased by >20% over the five-year period, with dramatic increases observed with fluoroquinolones, tobramycin, and imipenem (resistance increased by 34–37%). In 1998, 78% of isolates were susceptible to all four anti-pseudomonal agents and no isolate was considered multi-drug resistant. However, in 2002, only 27% of isolates were sensitive to all four of the drugs and 32% were considered multi-drug resistant. Multi-drug resistance in individual institutions may be significantly higher than rates reported in nationwide surveillance studies and may more accurately reflect the true magnitude of local resistance problems. On-going surveillance within individual institutions is critical for the selection of appropriate empiric antimicrobial therapy.