Here we present four clinical cases of immunocompromised patients experiencing bacteremia caused by Leptotrichia species in a few months with no common epidemiological link. Leptotrichia species are thin anaerobic gram-negative rods that inhabit multiple areas in the human body, including the oral microbiota. Many infections with Leptotrichia species occur in immunocompromised individuals classifying Leptotrichia species as opportunistic pathogens. Utilization of standard microbial identification methods of matrix-assisted laser-desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) initially yielded the same identification for all four Leptotrichia isolates as Leptotrichia buccalis. However, 16S ribosomal RNA sequencing confirmed the identification of only one of the four isolates as L. buccalis, while two of the four isolates were identified as Leptotrichia trevisanii. These four cases highlight the clinical importance of considering opportunistic infection in immunocompromised patients with unusual organisms considered members of the normal oral flora. J Microbiol Infect Dis 2022; 12(3):130-135.