In the past, hypothyroidism has been associated with an increased susceptibility to gastric cancer (GC). Although several epidemiological studies have corroborated this association, a precise mechanistic explanation remains elusive. In this study, this hypothesis was tested by using a large database of subjects who underwent upper endoscopy for various reasons. This was a retrospective, case-control, single-center study. Subjects with GC (cases) were compared with subjects without (controls), according to hypothyroidism status. Overall, the prevalence of GC was 0.73% in the total cohort and was significantly higher in males compared to females (1.4% versus 0.4%, p < 0.0001). Multivariate logistic regression analysis confirmed an increased risk in males with hypothyroidism (OR 5.10; p < 0.0001) after adjusting for potential confounders, especially H. pylori infection. Interestingly, only hypothyroidism and not treatment with levothyroxine was a significant predictor of GC, ruling out a possible direct carcinogenic effect of the replacement therapy. The present study suggests a male-restricted association of gastric carcinogenesis with a hypothyroid state. If the results of this study are confirmed by longitudinal studies, an attractive perspective could open up for the better management of males with concomitant hypothyroidism and a higher risk of GC.