Purpose: There is very little data on the effect of combining methods to better predict and improve oral antineoplastic adherence in cancer patients. The goal of this study was to evaluate the effectiveness of an intensive pharmacist intervention at the beginning of oral antineoplastic therapy versus nurse-led control group on adherence. Methods: This was a prospective, randomized, open-label controlled trial performed in a single center hematology/oncology outpatient service to compare the effectiveness of repetitive pharmacist educational intervention on adherence rates measured at four and eight weeks after prescribing oral antineoplastic medication compared to a nurse-led control group. Both groups included investigator pill counts and self-report adherence questionnaires. Results: Two-hundred patients were enrolled between 2009 and 2015. Fourteen of the 101 (14%) patients in the pharmacist group and 7 (7%) of the 99 patients in the nurse-led control group dropped out (p = 0.166). The majority of patients who remained in the study were 90-100% adherent to oral antineoplastic therapy in both groups. The pharmacist group slightly underperformed at Pill Count 2, possibly due to barriers for non-adherence. Statistically significant correlations associated with non-adherence were forgetfulness (p = 0.009), wanting to avoid side effects (p = 0.02), feeling depressed or overwhelmed (p = 0.032), or falling asleep before taking medication (p = 0.048) in both groups. Conclusion: The combination of pill count and patient self-report adherence is a way of improving oral antineoplastic adherence. However, significant barriers to adherence were identified such as forgetfulness, wanting to avoid side effects, feeling depressed or overwhelmed, and falling asleep before taking medications.