Infectious diseases like infective endocarditis (IE) may manifest or progress differently between sexes. This study sought to identify the differences in demographic and clinical characteristics among male and female patients with IE. Data were obtained from a newly developed registry comprising all adult patients with first IE admission at the four major tertiary cardiovascular centers in West Virginia, USA during 2014–2018. Patient characteristics were compared between males and females using Chi-square test, Fisher’s exact test, and Wilcoxon rank-sum test. A secondary analysis was restricted to IE patients with drug use only. Among 780 unique patients (390 males, 390 females), significantly more women (a) were younger than males (median age 34.9 vs. 41.4, p < 0.001); (b) reported drug use (77.7% vs. 64.1%, p < 0.001); (c) had tricuspid valve endocarditis (46.4% vs. 30.8%, p < 0.001); and (d) were discharged against medical advice (20% vs. 9.5%, p < 0.001). These differences persisted even within the subgroup of patients with drug use-associated IE. In a state with one of the highest incidences of drug use and overdose deaths, the significantly higher incident IE cases in younger women and higher proportion of women leaving treatment against medical advice are striking. Differential characteristics between male and female patients are important to inform strategies for specialized treatment and care.