This study reports on the development and psychometric properties of a new measure assessing therapist comfort in the home treatment context and the relationship between therapist comfort, related process variables, and therapist characteristics. Data were drawn from a longitudinal evaluation of 185 families treated by 51 therapists using Multisystemic Therapy (MST). Therapist comfort was measured at four time points. Psychometric evaluation indicated that the measure was internally and temporally consistent. Examination of the measure's validity indicated that therapists' feelings of safety and comfort during the provision of home-based treatment were associated with family neighborhood characteristics and family socioeconomic factors. Furthermore, the therapist's reported level of alliance (as measured by the Emotional Bonding subscale of the Working Alliance Inventory) was related to her/his feeling of comfort. Analyses also indicated that therapists with greater belief in the clinical utility of the MST model felt more comfortable when delivering MST. Together the results suggest that economically disadvantaged families treated in home and community settings may be most at risk for erosions in the therapeutic relationship over time as a function of lower therapist comfort. Because therapist comfort was associated with therapeutic alliance—a factor found to be associated with clinical outcomes across studies and treatment models—findings imply that psychotherapists should regularly examine their own level of comfort, especially when providing services in nontraditional settings, and that therapist comfort should be routinely assessed as part of clinical supervision and training.