Drawing on U.S. data from the Teaching and Learning International Survey (TALIS) 2018, this study first compared STEM and non-STEM teachers' self-efficacy in multicultural classrooms (TSMC), then identified the factors related to TSMC for each group of teachers, and lastly explored the similarities and differences among the factors. Results from general linear model univariate analysis revealed that STEM teachers scored significantly lower in TSMC than their non-STEM counterparts. Results from multilevel modeling analysis indicated that gender and professional development needs were significant predictors of TSMC for both groups; factors such as initial teacher preparation, professional development topics, and school instructional leadership emerged as significant predictors only for non-STEM teachers. The implications and significance of these results were discussed.