Objective: Control beliefs have been found to influence adaption to a cancer diagnosis. This study explored interrelationships among education, control beliefs, and health-related quality of life (HRQoL) in patients with breast, prostate, colorectal, and lung cancer and tested weather control beliefs act as mediators. Methods: Six hundred and five patients with breast (n = 205), prostate (n = 205), colorectal (n = 124), and lung (n = 71) cancer from two German cancer registries answered standardized questionnaires. Response rate was 54%. HRQoL was assessed with the EORTC QLQ-C30 core questionnaire and control beliefs (internal, external, and fatalistic) were evaluated using the IPC-questionnaire. Education was measured on a scale ranging from 1 to 8. Data were analyzed using multiple mediation models. Results: There was a positive correlation between education and HRQoL. Internal beliefs were positive and external beliefs were negative correlated with HRQoL. Internal control beliefs mediated the relationship between education and global health-related quality of life (.299, CI.122,.531), physical functioning (.272, CI.110,.486), emotional functioning (.325, CI.120,.578), and pain (-.288, CI −.558, −.094). External and fatalistic control beliefs did not act as mediators. Conclusion: Patients with low education feel they have less control over their cancer disease and consequently a poorer health-related quality of life.