Background: Clinical evidence points to patientperceived difficulties and compliance problems in implementing early insulin therapy. Therefore, individual treatment aims are necessary to optimize diabetes therapy, as currently acknowledged by the new ADA/EASD guidelines. Better characterization of patient-perceived difficulties in the implementation of early insulin treatment may contribute to improved compliance and optimal tailoring of treatment regimens for the individual patient. Objective: To assess differences in quality of life (QoL) and patient-perceived difficulties in health care with every addition of oral hypoglycemic agents (OHAs) and insulin therapy. Methods: The analysis was conducted on a cross-sectional sample of 714 diabetic patients treated with OHAs or with insulin once or twice daily. Differences in diabetes-specific QoL, overall QoL, and perception of difficulties associated with specific diabetes treatment attributes were evaluated using trend analysis and comparisons between groups. The contribution of each diabetes treatment attribute to QoL measures and glycemic control was also assessed. Results: No significant differences were found in QoL measures among patients treated exclusively with OHAs when these patients were assessed by the number of oral agents, irrespective of the degree of glycemic control. Better controlled patients treated with 2 OHAs, compared with poorly controlled patients treated with a single OHA, had a lower perception of difficulties associated with diabetes treatment attributes. Poorly controlled patients treated with 2 OHAs and better controlled patients treated with 3 OHAs had similar QoL and perceived difficulties with care. However, the insulin-based alternative was consistently associated with a significantly higher perception of pain and lower overall QoL when compared with the oral regimens. Multivariate models accounted for 52% and 32% of the variance in QoL measures. Conclusion: From the patients’ perspective, oral therapy is the preferred strategy for attaining the treatment goals since the addition of OHAs was not associated with lower QoL or patient-perceived difficulties with care. If early insulin treatment is considered, physicians should address specific diabetes treatment characteristics, mainly the issue of pain, to promote improved QoL and disease control.