The present study was undertaken with the aim of evaluating the effect of multiple insulin injection therapy with an insulin pen in a large population of type 1 and type 2 diabetes patients and to investigate which factors predict a favorable response to the therapy change. We included 100 type 1 and 51 type 2 patients with a minimum diabetes duration of 1 year who were followed for at least 3 years after changing from conventional insulin regimens to multiple insulin injection therapy with the pen. Both type 1 and type 2 patients were significantly improved with respect to metabolic control at 3 months. After 1 year type 1 patients were no longer significantly improved compared to baseline. In type 2 patients a significant improvement was sustained for a longer period but at 3 years HbA1c had reverted towards the baseline level. Both type 1 and type 2 patients experienced a significant increase in body weight. Baseline metabolic control was strongly and inversely related to subsequent decline in HbA1c in both type 1 and type 2 patients. Those with initial poor control had a sustained improvement throughout follow-up, whereas those with initial very good control deteriorated significantly. No sustained change was noted in those in intermediate control. In addition, in type 1 patients a high body mass index at baseline was a weak negative predictor for improvement. In type 2 patients a longer duration of diabetes was a favorable factor. Both type 1 and 2 patients in poor control may be expected to benefit from multiple injection therapy.