This exploratory study examined the extent to which the effectiveness of instructional interactions varies among classroom social settings (i.e., large group, free choice, meals, and routines), learning activities (i.e., shared reading, literacy, math, science, social studies, and esthetics), or their combination. Participants were 314 preschool teachers primarily serving children from low-income backgrounds. Instructional interactions were measured in multiple cycles across one day of classroom observation as teachers engaged in a variety of settings and learning activities. Linear mixed models indicated that the effectiveness of teachers' instructional interactions was generally higher in the large group setting than in free choice, meals, and routine settings. When considering settings and learning activities in combination, teachers displayed the most effective global instructional interactions when leading science activities in large group or free choice settings, and the most effective literacy-focused interactions during large group literacy activities. (author abstract)