There are few data regarding the prevalence and trends of antibiotic resistance to Klebsiella pneumoniae in Saudi Arabia over time. Thus, we evaluated the prevalence and the trends in antibiotic resistance of K. pneumoniae at the Saudi Aramco Medical Services Organization over a 6-year period. This was a retrospective study of the in vitro pattern and trends of antibiotic resistance of K. pneumoniae from 1998 to 2003. A total of 3070 distinct isolates of K. pneumoniae were analyzed. Hospital-acquired isolates were more resistant to the tested antibiotics than the outpatient isolates. The resistance rates to cefazolin, trimethoprim-sulfamethoxazole, and ciprofloxacin were 10.8% (n = 79/730), 5% (n = 103/2093), and 15.8% (n = 93/586) for hospital-acquired isolates; and 11% (n = 216/1964), 9.6% (n = 60/624), and 4.4% (n = 68/1526) for outpatient isolates. Resistance to ceftriaxone and ceftazidime was detected in 5.6% (n = 37/659) and 13.8% (n = 24/174) of hospital-acquired isolates and in 1% (n = 17/1713) and 2.7% (n = 6/219) of outpatient isolates, respectively. All tested isolates were susceptible to imipenem. Resistance to three or more classes of antibiotics was present in 1.7% (n = 8/468) of the hospital-acquired isolates and in 0.6% (n = 9/1389) of the outpatient isolates. The data showed increased resistance rates of hospital-acquired isolates of K. pneumoniae to ceftriaxone, gentamicin, and ciprofloxacin; the data also showed that hospital-acquired, rather than outpatient isolates, were more likely to be resistant to multiple antibiotics.