The genetics of microbial pathogens have been extensively studied, but there has been little work on human genetic susceptibility to surgical site infection (SSI). We analyzed a large genealogical population database to study the familial contribution to SSI. We analyzed 651 individuals with International Classification of Disease, Ninth Revision codes indicating the presence of SSI. Matched hospital controls were randomly selected from the database based on birth year, sex, and birthplace. The average relatedness of all possible pairs of cases and separately of controls (×1000 sets) was compared empirically. The relative risk (RR) for SSI was estimated by comparing the number of observed affected individuals among the relatives of cases to the number of affected individuals observed among relatives of matched hospital controls. The genealogical index of familiality test for patients with SSI showed significant excess relatedness (p < 0.010); this excess was still observed when close relationships were ignored (p = 0.019). The RR for third-degree relatives of cases was significantly elevated (1.62, p = 0.029). The significant excess relatedness and the significantly elevated RR to distant relatives support a genetic predisposition to acquiring SSI.