The prevalence of treatment-resistant depression (TRD) among patients with pharmaceutically treated depression (PTD) varies greatly in publications. The aim of this study is to estimate the prevalence of TRD using 2 large claims databases in the US. This cross-sectional study used data from the Humana and Optum databases. Patients aged ≥ 18 years who had at least 1 diagnosis of major depressive disorder (- codes: F32.xx, F33.xx) and 1 antidepressant prescription filled in 2018 were identified as having PTD. Among patients with PTD, TRD was defined as experiencing failure of treatment with at least 2 antidepressants with ≥ 4 weeks of adequate treatment. We estimated the age- and gender-standardized prevalence of TRD and then used logistic regression to investigate if TRD risk varies by age, sex, race, and geographic region. Finally, we described the timeline of TRD development in incident PTD patients. We identified 296,055 and 277,941 patients with PTD in the Humana and Optum databases, among whom 17,640 (6.0%) and 16,131 (5.8%) had TRD. After age and sex standardization, TRD prevalence among PTD patients was 6.8% in Humana vs 5.8% in Optum. Females, middle-aged adults, and White patients had higher risk of TRD. The median time from index antidepressant use to TRD was about 6 months in incident PTD patients. The prevalence of TRD among patients with PTD was similar in the 2 databases. TRD prevalence varies by sex, race, and age, with a higher prevalence in females, White patients, and those in the age group of 45-64 years. However, the absolute differences were small.