Background: Due to the disease complexity and life-threatening nature, many patients with cancer seek a second opinion (SO) pursuing the best help to navigate through their disease journey. In this study, we evaluated the reasons for seeking SO, challenges, and outcome. Methods: This is a cross section study using a 62-item questionnaire inquiring about patients’ demographics, reasons, challenges, comparison between primary specialists (PS) and SO specialists, and SO outcome. Patients with cancer diagnosis served at the collaborating institutions between January and November 2022 completed the survey either on paper copy or online via provided link to a SurveyMonkey form. Results: 425 surveys were sent, and 205 (48%) patients responded. Median age at diagnosis was 67 years (19-90), 80% were males, 93% were white and 36% had private insurance. A total of 137 (67%) sought a SO. The most frequent reason to seek SO was lack of confidence in treatment plan (52%). Recommendations of SO were different from PS recommendations in 48% of the cases. Predictors of seeking SO on a multivariate analysis (MVA) were diagnosis after 2015, having metastatic disease, and having private insurance. 54% of the those sought SO transferred care to other physicians, 43% to the ones who provided SO. The MVA of factors related to patient characteristics revealed that having genitourinary malignancies, metastatic disease, and private insurance were predictors of changing PS. Factors related to PS performance are depicted in Table 1. Conclusions: A high percentage of patients received SO changed their PS to the physicians who provided the SO. Empathy and confidence are essential to maintain the relation with physician. Social determinants of health such as insurance has significant impact on seeking SO and changing PS.