Few studies have explored the relationship between health literacy (HL) and trial participation. In this context, we aimed to study this relationship in French cancer patients. We used data from the French national VIe après le CANcer (VICAN) survey. Two questionnaire items focused on previous invitations to participate in clinical trials and subsequent enrollment. The Single Item Literacy Screener was used to measure functional HL. In total, 1954 cancer patients responded to both VICAN surveys (two and five years after diagnosis). Mean age was 54.1 ± 12.7 years at diagnosis, and 37.6% were classified as having limited HL. One in ten (10.3%) respondents reported having been previously invited to participate in a clinical trial. Of these, 75.5% had enrolled. Limited HL was associated with fewer trial invitations but not with enrollment once invited. Multivariate analysis confirmed the negative effect of limited HL on clinical trial invitation (adjOR = 0.55 (0.39 to 0.77), p < 0.001) after adjustment for multiple characteristics. Patients with limited HL received fewer invitations to participate in trials but were likely to enroll when asked. Addressing HL is necessary to create a more inclusive health system and to reduce inequalities not only in access to innovative cancer care, but to health inequalities in general.