To identify overall costs generated by surgical site infections (SSI) patients, including indirect costs. A prospective study of case series of patients who have undergone major surgical treatment was undertaken. Patients who suffered SSI were compared with controls (nested case-control design). Centers for Disease Control and Prevention definitions were followed and SSI established. Overall costs and indirect related morbidity/mortality costs were estimated. The study was performed in a general, tertiary hospital (Valencia, Spain) for 4.5 years. Surgical site infections patients were 9.02% of the total people who underwent surgery. Their stays were prolonging by 14 days, and resources were used more intensely and for longer periods than in controls. Excess hospital costs were $10,232 per patient of which 37% corresponded to prolonged stays. Health costs only accounted for 10% of overall costs; $97,433 per patient including indirect social costs. Studies merely assessing excess costs due to prolonged stays of SSI patients do not reflect the entire scenario as they simply represent 35% of real hospital costs. A comprehensive appraisal shows that total healthcare expenditures represent a tenth of overall costs, which strengthens the claims that investment in preventing SSI would be highly cost-effective.