Background and aim This study constitutes an initial attempt at elucidating the relationship between quality of life (QoL), health status and psychological distress in patients with diabetes mellitus (DM) in Greece, by comparing patients with DM registered at a rural primary healthcare centre (PHCC) and those attending a diabetes outpatient clinic (DOC) at an urban hospital.Methods Cross-sectional study. Participants were consecutive, consenting patients with a known history of type 2DM(T2 DM), currently registered at either of the two centres. All patients were administered the Short Form-36 version 2 (SF-36 v2) and the Problem Areas In Diabetes (PAID) questionnaire, and information in relation to socio-demographic data and clinical characteristics were also obtained.Results Patients with DM had a lower QoL over all domains when compared with general population normative data. In addition, mean scores for the SF-36 v2 Physical Component Summary (PCS) and Mental Component Summary (MCS) and six subscales of the SF-36 v2 demonstrated significant differences between the two participating centres (P < 0.0001). The mean PAID score was 19.18 (±15.58) for patients from the PHCC, versus 40.19 (±17.36) for the DOC (P < 0.0001). Lower scores on the MCS of the SF-36 v2, and higher scores on PAID in patients with T2 DM were related to major co-morbidities, insulin use and duration of DM.Conclusions Patients with T2 DM from the urban DOC had significantly higher levels of distress and consequently lower levels of QoL compared with patients from the rural PHCC. The findings from this study may have important implications with regard to the individualisation of patient care in Greece, and encouragement of patient participation in the treatment process.