In 2015, participating US Emergency Departments (EDs) reported approximately 2.8 million visits related to skin and soft tissue infections (SSTIs). Studies indicate that there may be disparities by patient sex in physician treatment guideline adherence rates as a result of a gender bias during physician-patient interactions; however, only two epidemiologic studies have investigated the role of patient sex in guideline adherence rates for SSTIs. These prior studies were limited in size and covariate assessment. Thus, the magnitude and direction of the effect of patient sex is uncertain, warranting further research. Therefore, we conducted a large prospective study to elucidate the role that patient sex plays in guideline adherence rates among physicians for non-purulent cellulitis at two UMass Memorial Health Care Group EDs in 2017. Data on treatment and sex was abstracted from electronic medical records. Compliance with treatment guidelines was based on 2014 Infectious Disease Society of America (IDSA) guidelines. Adjusted multinomial regressions indicated that female patient sex was associated with lower prevalence of overtreatment (POR=0.72, 95%CI: 0.57-0.92). In contrast, female physician sex was significantly associated with higher prevalence of overtreatment (POR=1.48, 95%CI: 1.16-1.87), but did not affect the relationship of patient sex with overtreatment (P-interaction=0.80). Awareness of differential treatment by patient sex may improve physician adherence to guidelines. This study contributes to a growing body of literature elucidating the role of sex in medical decision making and is the first to account for both patient and physician sex as well as relevant covariates in studies regarding cellulitis treatment.