Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most widespread and dangerous pathogens in healthcare settings. We carried out this case-control-control study at a tertiary care hospital in Guangzhou, China, to examine the antimicrobial susceptibility patterns, risk factors and clinical outcomes of MRSA infections. A total of 57 MRSA patients, 116 methicillin-susceptible Staphylococcus aureus (MSSA) patients and 102 S. aureus negative patients were included in this study. We applied the disk diffusion method to compare the antimicrobial susceptibilities of 18 antibiotics between MRSA and MSSA isolates. Risk factors of MRSA infections were evaluated using univariate and multivariate logistic regression models. We used Cox proportional hazards models and logistic regression analysis to assess the hospital stay duration and fatality for patients with MRSA infections. The MRSA group had significantly higher resistance rates for most drugs tested compared with the MSSA group. Using MSSA patients as controls, the following independent risk factors of MRSA infections were identified: 3 or more prior hospitalizations (OR 2.8, 95% CI 1.3-5.8, P = 0.007), chronic obstructive pulmonary disease (OR 5.9, 95% CI 1.7-20.7, P = 0.006), and use of a respirator (OR 3.6, 95% CI 1.0-12.9, P = 0.046). With the S. aureus negative patients as controls, use of a respirator (OR 3.8, 95% CI 1.0-13.9, P = 0.047) and tracheal intubation (OR 8.2, 95% CI 1.5-45.1, P = 0.016) were significant risk factors for MRSA infections. MRSA patients had a longer hospital stay duration and higher fatality in comparison with those in the two control groups. MRSA infections substantially increase hospital stay duration and fatality. Thus, MRSA infections are serious issues in this healthcare setting and should receive more attention from clinicians.