The key role of an intact gastric acid secretion for subsequent intestinal T 4 absorption is supported by an increased requirement of thyroxine in patients with gastric disorders. A better pH-related dissolution profile has been described in vitro for softgel T 4 preparation than for T 4 tablets. Our study was aimed at comparing softgel and tablet T 4 requirements in patients with gastric disorders. A total of 37 patients with gastric-related T 4 malabsorption were enrolled, but only 31 (28F/3M; median age = 50 years; median T 4 dose = 2.04 μg/kg/day) completed the study. All patients were in long-lasting treatment (>2 years) with the same dose of T 4 tablets when treatment was switched to a lower dose of softgel T 4 capsules (−17 %; p = 0.0002). Assessment of serum FT 4 and TSH was carried out at baseline and after 3, 6, 12, and 18 months after the treatment switch. In more than 2/3 of patients (good-responders n = 21), despite the reduced dose of T 4 , median TSH values were similar at each time point ( p = 0.3934) with no change in FT 4 levels. In the remaining patients (poor-responders n = 10), TSH levels were significantly higher at each time point than at baseline ( p < 0.0001). To note, in five of them intestinal comorbidity was subsequently detected. Comorbidity associated with poor-responders status was the only significant predictor in multivariate analysis (OR = 11.333). Doses of softgel T 4 capsules lower than T 4 tablet preparation are required to maintain the therapeutic goal in 2/3 of patients with impaired gastric acid secretion.