Clinical guidelines developed from randomized controlled trials (RCT) recommend standard treatments for physicians to treat their patients. However, RCT are usually conducted among younger or healthier populations. Patients who did not participate in clinical trials, such as the elderly or patients with comorbidities, might not be suitable for the standard treatments; instead non-standard treatments can be an alternative treatment option to provide clinical benefits. Physicians are key stakeholders in determining the use of non-standard treatments in clinical practice. While a number of studies have reported on the use of non-standard treatments, little is known about factors associated with a physician’s decision to use non-standard treatments and which information sources are associated with their use. The objectives of this study were to identify factors associated with a physician’s decision to use non-standard treatments and to investigate which information sources were associated with their use. This study applied Rogers’ theory of diffusion of innovation to posit that a physician’s decisions to use non-standard treatments are a function of 1) the perceived advantages of non-standard treatments (effectiveness and toxicity), 2) the sources of information (scientific sources, professional contacts, patient demands, and commercial sources), 3) physician characteristics (years of practice, specialty, innovativeness, and practice experience), and 4) practice settings (practice location, academic affiliation, types of facility, and practice size). This study implemented a convergent parallel mixed-method approach consisting of interviews and surveys to address the objectives. For this study, a convenience sample of 10 medical oncologists was interviewed in January and February 2017. Interviews were transcribed and coded using a coding system based on the theoretical model of this study. Case reports were created to summarize each interview. The content analysis and multi-case analysis were both conducted to describe variable-level factors and contrast and compare factors within and across groups. Surveys were distributed to 1,500 medical oncologists and hematologists who currently practice in eight states across the Midwest. Dillman’s tailored design method was used to guide survey development and administration. The survey examined oncologists’ use of non-standard treatments in elderly patients with diffuse large B-cell lymphoma (DLBCL). Factorial survey design was applied to construct six hypothetical patient vignettes representing a variety of patient age and comorbidity. The dependent variable was whether a physician recommended a non-standard treatment to each vignette. Independent variables were selected from the theoretical model. The descriptive and frequency statistics were conducted for each survey item. The reliability tests were used to evaluate internal consistency of multi-item measures. Generalized Estimating Equations (GEE) were used to test the influence of factors on a physician’s decisions to use non-standard treatments. Among ten interview participants, three were open and five were intermediate open toward using non-standard treatments. Approximately 41.5% of survey participants recommended non-standard treatments for two or more vignettes. Both interviews and surveys showed that sources of information were key factors affecting oncologists’ use of non-standard treatments. In particular, interviewed oncologists used various information sources to justify their use of non-standard treatments such as early phase clinical trials or colleagues’ suggestions. Survey data showed that oncologists who placed higher importance on scientific sources were less likely to use non-standard treatments although scientific or medical journals were the top sources where they learned about rituximab with non-anthracyclines. In vignettes involving patients with rheumatoid arthritis with chronic neutropenia, those who placed a higher importance of professional sources were more likely to use non-standard treatments. Additionally, interview data showed that oncologists who have a sub-specialty, practice in academic settings, have high patient volume, have positive past experience with non-standard treatment and were aware of colleagues’ use non-standard treatments were relatively more open toward using non-standard treatments. Survey data showed that oncologists who agreed that rituximab with non-anthracyclines has a safer toxicity profile than rituximab with anthracyclines, those who commonly encounter younger patients, and those who had more years since graduating from medical school were more likely to use non-standard treatments. In addition to patient characteristics such as comorbidity, physicians’ characteristics and their sources of information are influential to the decision of using non-standard treatments.