Bariatric surgery (BS) is a highly effective therapy for morbid obesity, yet with a wide inter-individual variability on weight-loss responses. To determine genetic influence on weight loss after BS we compared the within-pairs difference in maximum percentage excess weight loss (%EWL) and the within-pairs %EWL differences over a mean follow-up of 53.6 ± 36.4 months between 47 pairs of first-degree relatives and 47 genetically unrelated control pairs. Within-pairs maximum %EWL difference was similar between first-degree related pairs and control pairs (p = 0.100). Within-pairs %EWL difference increased through follow-up (p < 0.001). However, effect of time was different depending on genetic background (ptime*group = 0.001). Increased variability in mid-term weight response was present in unrelated pairs but not in first-degree pairs (p < 0.001 and p = 0.535, respectively). To assess shared environment influence, 16 married couples were identified and 16 unrelated and non-cohabiting matched pairs were also analyzed. In these analysis within-pairs difference in %EWL also increase over time (p = 0.025) but no group by time effect was observed (ptime×group = 0.177). In conclusion first-degree related participants showed closer weight trajectories after BS time than genetically unrelated subjects. Genetic background might partially explain the variability in mid-term weight-loss after BS.