Aim: To investigate treatment satisfaction with semaglutide, a once-weekly glucagon-like peptide-1 receptor agonist, versus placebo/active comparators in the SUSTAIN clinical trial programme. Methods: In SUSTAIN 2–5 and 7, the Diabetes Treatment Satisfaction Questionnaire was used to evaluate patient-perceived treatment satisfaction, hyperglycaemia and hypoglycaemia. Post hoc subgroup analyses were conducted to explore the effects of gastrointestinal adverse events (GI AEs), weight loss (≥5%) or achieving glycaemic (HbA1c < 7%) targets on treatment satisfaction. Results: Overall treatment satisfaction increased from baseline to end of treatment with all treatments across trials. Improvements were significantly greater with semaglutide versus comparators/placebo in SUSTAIN 2–5 (all P < 0.05), and generally greater in patients who achieved versus did not achieve weight loss and glycaemic targets, often with greater improvements with semaglutide 1.0 mg versus comparator/placebo in both weight loss groups. In SUSTAIN 7, improvements in overall treatment satisfaction were generally similar between semaglutide and dulaglutide, irrespective of weight loss or glycaemic control. In SUSTAIN 7, changes in overall treatment satisfaction score were generally lower in patients with versus without GI AEs at week 16 (except dulaglutide 0.75 mg), but similar by week 40. Perceived hyperglycaemia was significantly reduced from baseline to end of treatment with semaglutide versus all comparators/placebo (all P < 0.05). No differences between treatments were observed for perceived hypoglycaemia. Conclusions: Semaglutide was associated with significantly greater (SUSTAIN 2–5) or similar (SUSTAIN 7) improvements in overall treatment satisfaction versus comparators/placebo. Improvements in overall treatment satisfaction were generally greater in patients achieving versus not achieving treatment targets. Clinicaltrials.gov: NCT01930188 (SUSTAIN 2), NCT01885208 (SUSTAIN 3), NCT02128932 (SUSTAIN 4), NCT02305381 (SUSTAIN 5) and NCT02648204 (SUSTAIN 7). EudraCT: 2012–004827-19 (SUSTAIN 2), 2012–004826-92 (SUSTAIN 3), 2013–004392-12 (SUSTAIN 4), 2013–004502-26 (SUSTAIN 5) and 2014–005375-91 (SUSTAIN 7).