Homicide is a prevalent cause of death among sex workers, given their increased risk of violence due to proximity to criminal activities such as drug trade and human trafficking. This study analyzes homicide data from the National Violent Death Reporting System (NVDRS) covering 49 US states, the District of Columbia, and Puerto Rico from 2012 to 2020. Case inclusion criteria included: (1) manner of death of homicide, and (2) sex work‐related circumstance. Descriptive analyses examined victim and injury characteristics, suspect information, and circumstances. The study identified 321 sex work‐related homicides (54% female, 41% male, 6% transgender). Among female victims, 94% were sex workers, and 54% of their suspects were clients. Money conflicts (23%) and other crimes (30%), most often in progress, commonly precipitated homicides of female victims. Substance use problems were reported in 49% of female victims, with 25% of their suspected perpetrators reportedly using substances in the preceding hours. For male victims, 54% were clients and 9% were sex workers. Suspects in male homicides were primarily sex workers (34%) or individuals engaged in sex work‐adjacent criminal activities (36%). Money conflicts (49%), other crimes (47%) most often in progress, and sex trafficking involvement (25%) commonly precipitated homicides with male victims. Transgender sex worker victims were mostly transfeminine (94%) and non‐Hispanic black (89%). Money conflicts (78%) most commonly precipitated homicides among transgender sex worker victims. These findings can inform prevention strategies addressing underlying risk factors for persons involved in sex work.