Adherence, medication wastage, and reduction in hospital admissions were investigated in a retrospective test-control study design for patients enrolled in the oral chemotherapy cycle management program (CMP), a program that offers clinical support, dose monitoring, and early identification of side effects for patients on select oral chemotherapy. Patients who initiated oral chemotherapy with sorafenib, sunitinib, or erlotinib during June 2008 through December 2009 and who were enrolled in the CMP were included as a test group. Patients who initiated oral chemotherapy with these drugs using Walgreens Specialty Pharmacy during January 2007 through May 2008 and were not part of the CMP were included as control group 1, and patients from a national payor database who initiated therapy with sorafenib, sunitinib, or erlotinib during June 2008 through August 2010 were included as control group 2. Compared with control group 1, patients in the CMP group showed no significant differences with regard to their possession ratios (P > .05), but demonstrated significantly higher persistency rates (P < .05) at the end of 6 months follow-up. For patients in the CMP group who discontinued therapy, approximately 34% could have experienced reduced wastage had they been on a split medication plan. Patients who are monitored closely and able to identify serious side effects early can avoid complications leading to hospitalizations. The study showed potential savings on drug costs because of a split-fill medication plan, and savings from reduced hospitalization associated with timely identification and management of severe side effects. A clinical program, such as CMP, effectively improves adherence and reduces wastage and hospitalizations for oral chemotherapeutic agents, realizing potential cost savings to both payors and patients.