Soothing conversation (SC) is particularly promising for symptom management during outpatient chemotherapy. However, we know little about the profile of patients who are most likely to benefit from this intervention. To gain a better understanding of the profile of patients most likely to benefit from SC to reduce symptom burden during outpatient chemotherapy. We performed a multimethod secondary analysis of 2 data sets: the first gathered during a quantitative pilot trial investigating the impact of SC on patients' symptom fluctuations during chemotherapy perfusion (n = 24); the second derived from qualitative interviews about nurses' experiences with SC in this context (n = 6). Secondary quantitative analysis suggests that symptom control with SC is more effective in older patients, reporting lower education, widowed status, work incapacity, advanced cancer, and undergoing chemotherapy perfusion for less than 1 hour. According to nurses' interviews, SC could best benefit patients (1) prone to anxiety and fear, (2) with unalleviated pain, (3) who are unaccompanied during treatment, and contrary to what was shown with quantitative data, (4) undergoing longer perfusion duration. Although this study provides valuable insights, much work remains to be done to fully understand the factors that predispose patients to respond positively to SC during outpatient chemotherapy. This study extends previous research on the effectiveness of SC for symptom management during outpatient chemotherapy by comparing nurses' experience with the intervention to patients' results. Results could be used to inform the assignment and delivery of supportive communication-based interventions during chemotherapy protocols.