Objectives: To compare patients with type 1 diabetes mellitus (T1DM) or cystic fibrosis-related diabetes (CFRD) on frequency and severity of symptoms suggestive of hypoglycaemia and diabetes-specific health-related quality of life (HRQoL). Methods: This was a cross-sectional comparison study. Participants with T1DM or CFRD completed a questionnaire that assessed symptoms suggestive of hypoglycaemia and diabetes-specific HRQoL, and recorded episodes of low blood sugars in a prospective diary. Comparisons of responses were conducted, and Pearson product correlations were determined between HRQoL scores and other continuous variables. HRQoL scores were compared between the groups after adjusting for confounding factors. Results: Diabetes in cystic fibrosis (CF) patients had a less negative impact on HRQoL than in T1DM patients. Both groups experienced hypoglycaemia, but loss of consciousness or needing help was more common in T1DM patients. Symptoms suggestive of hypoglycaemia were less of a problem for CFRD patients in terms of severity, with T1DM patients having more neuroglycopenic symptoms. Discussion: Although the same percentage of patients in both groups reported experiencing hypoglycaemia, severity (e.g. symptoms and loss of consciousness) was higher for those with T1DM. Symptoms of hypoglycaemia appear to have a significant impact on HRQoL, and could account for the worse HRQoL in T1DM patients.