Background: Unlike the tablet (TAB) formulation, liquid L-T4 (LIQ) is directly absorbed in the intestine. The aim of this study was to assess whether LIQ was superior to TAB, such that it would overcome the interference induced by co-ingestion of multiple interfering drugs (ID). Methods: In this prospective cohort study, we recruited 11 patients with apparent reduced TAB absorption due to >= 2 ID, and switched them to LIQ while maintaining the daily dose and the co-ingestion of the ID. Serum TSH was assayed at least twice every eight weeks. Results: Serum TSH was significantly lower on LIQ compared with TAB (P<0.0001), in patients who took L-T4 for either replacement (P=0.002) or TSH-suppression (P<0.0001). This difference was evident already at the first measurement post-switch (P=0.008 or P=0.03). Regardless of the purpose of L-T4 therapy, patients who took two ID had lower serum TSH on LIQ compared with patients who took three ID (P=0.0006). Interestingly, 2/3 patients who failed to reach target TSH levels while on LIQ took three ID. Conclusions: LIQ overcomes the concurrent interference exerted by the ingestion of multiple ID. In such cases, switching from TAB to LIQ permits patients to reach target TSH within 8weeks.