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Background The use of vaginal white blood cell (WBC) counts to predict sexually transmitted infections (STIs) in the emergency department (ED) is incompletely characterized. Objectives Our objective was to assess the relationship between vaginal wet preparation WBC counts and STIs and to determine whether WBC counts of at least 11 WBCs per high-power field (HPF) could be useful for identifying STIs in women in the ED. Methods Female ED patients 18 years or older who were evaluated in a single health system between April 18, 2014, and March 7, 2017, and had a genital wet preparation WBC result were retrospectively examined using univariable and multivariable analysis. Results Vaginal wet preparation WBC counts were examined for 17,180 patient encounters. Vaginal WBC counts of at least 11 WBCs/HPF were associated with increased odds of having gonorrhea, chlamydia, or trichomoniasis. When this threshold was used for the diagnosis of each STI, sensitivity ranged from 48.2% to 53.9%, and specificity ranged from 67.2% to 68.8%. Conclusion Women with STIs are more likely to have higher vaginal WBC counts. However, higher vaginal wet preparation WBC counts in isolation have limited diagnostic utility for gonorrhea, chlamydia, and trichomoniasis. Incorporation of age, urine leukocyte esterase results, and vaginal WBC counts provided a better predictor of an STI than vaginal WBC counts alone.