Introduction: Cancer is a chronic debilitating disease that unnerves patients, communities, and nations. At some point in cancer patient’s disease experience, chemotherapy is used, and the patient is expected to adhere to treatment to improve survival and quality of life. Methods: This multisite Cluster Randomized Trial (CRT) evaluated the effectiveness of mobile phone Short Message Service (SMS) support on the adherence to treatment schedules among adult cancer patients in Kenya. Data was collected using questionnaires. Ethical approvals were obtained from relevant Ethical Review Boards (ERBs). Results: The mean adherence was 83%. There was a significant difference between treatment arms in relation to the adherence. The intervention arm had a higher mean adherence difference, M = 3.913, 95% CI 2.632 - 5.193, t (402) = 6.006, p ≤ 0.001), with Cohen’s d = 0.60. Although not significant, (χ 2dd = 0.151, df = 1, p = 2.064), more women were perfect adheres than males. Perfect adherers were satisfied with SMS support (χ 2dd = 7.620, df = 1, p = 0.06), were in the intervention arm (χ 2dd = 22.942, df = 1, p ≤ 0.001), and had trust in the care provider (χ 2dd = 10.591 p ≤ 0.001). SMS support was not significant in the multivariate analysis but had an estimated effect size of 0.958 (z = 1.424, p = 0.154, CI = 0.242 - 3.781), indicating that mean adherence was slightly better in the presence of the intervention. Conclusions: SMS-support intervention has demonstrated superiority in influencing adherence. Further, health system-related factors have a significant influence on the adherence to chemotherapy treatment. Interventions to re-design health systems that are responsive to unmet care needs of cancer patients must be explored.