Introduction Methicillin-resistant Staphylococcus aureus infections have been increasingly reported in patients with cystic fibrosis (CF) who have progressive deterioration in their pulmonary function. Objectives To determine the prevalence of MRSA infections in CF in a tertiary care center in Saudi Arabia. Methodology This is a retrospective chart review conducted as part of the CF registry data from 1 January 2002 to 1 June 2016. All patients with confirmed CF of all age groups who had a respiratory culture positive for MRSA were included in the study. Results Among 385 patients with CF who had respiratory samples, 43 (11%) were positive for MRSA at a mean age of 10.4 ± 7.2 years. Twenty-two patients out of the 43 (51%) were treated with different regimens: nasal Bactroban in 13/22 (59%); a combination of nasal Bactroban, oral vancomycin, and rifampicin for 2 weeks in 5 patients (23%); Bactroban and linezolid in one patient (5%); and oral vancomycin and rifampicin in 3 patients (14%). Eight out of the 22 treated patients (36%) achieved MRSA eradication. Six out of the 22 treated (27%) had experienced MRSA recurrence within 3–6 months, and another 5/22 (23%) continued to have MRSA colonization up to 2–4 years of follow-up despite using a proper eradication protocol. Twelve out of the 43 (28%) patients with MRSA infection died. Conclusion MRSA infection in our population with CF is common. Therefore, an eradication protocol should be instituted at an early stage to prevent chronic colonization. Children with persistent MRSA colonization have high morbidity and mortality rate.