High school co-teachers prepare students with and without disabilities to earn content credits for graduation, with instructional effectiveness influenced by multiple factors. In this study, teacher self-efficacy and personal compatibility were examined as potential predictors of active involvement in instruction. The moderating effect of personal compatibility on the relationship between teacher self-efficacy and active involvement in instruction was also examined. One hundred twenty-seven co-teachers of students with learning disabilities and other high-incidence disabilities participated. Active involvement in instruction was significantly higher for general educators than for special educators. Results of Actor-Partner Interdependence Model (APIM) analyses revealed teacher self-efficacy was predictive of active involvement in instruction for general educators but not for special educators. Results of APIM with moderation found personal compatibility did not significantly moderate the relationship between teacher self-efficacy and active involvement in instruction for general or special education co-teachers. Implications for co-teaching practices are provided.