Policy-makers have recommended universal screening to reduce nosocomial methicillin-resistant Staphylococcus aureus (MRSA) infection. Risk profiling of MRSA carriers and rapid PCR tests are now available, yet cost-effectiveness data are limited. The present study assessed the cost-effectiveness of universal PCR screening on admission to surgery. A decision analysis model from the hospital perspective compared costs and the probability of any MRSA infection across three strategies: (i) PCR screening; (ii) screening for risk factors (prior hospitalization or antibiotic use) combined with pre-emptive isolation and contact precautions pending chromogenic agar results; and (iii) no screening. Clinical data were taken from studies at a Swiss teaching hospital as well as from published literature. Costs were derived from hospital accounting systems. Compared to no screening, the PCR strategy resulted in higher costs (CHF 10503 vs. 10358) but a lower infection probability (0.0041 vs. 0.0088), producing a base-case incremental cost-effectiveness ratio of CHF 30784 per MRSA infection avoided. The risk factor strategy was more costly yet less effective than PCR, although, after varying epidemiologic inputs, the costs and effects of both screening strategies were similar. Sensitivity analyses suggested that on-admission prevalence of MRSA carriage predicts cost-effectiveness, alongside the probability of cross-transmission, and the costs of MRSA infection, screening and contact precautions. Although reducing the risk of MRSA infection, universal PCR screening is not strongly cost-effective at our centre. However, local epidemiology plays a critical role. Settings with a higher prevalence of MRSA colonization may find universal screening cost-effective and, in some cases, cost-saving.