Depot somatostatin analogs are now increasingly being prescribed as adjuvant and primary therapy for the treatment of acromegaly. Previous studies have shown them to be both effective and safe, suppressing GH levels to less than 2 μg/liter in 50–65% of cases and normalizing serum IGF-I levels in 65%. However, published data on their long-term efficacy and safety is scanty. We analyzed data from 22 patients (16 female and 6 male) treated with Sandostatin LAR or Lanreotide for an average of 41 months (range 12–89). Three patients had previously been treated with surgery, two with radiotherapy, and seven with both. Ten patients had received primary medical therapy. Mean pretreatment GH levels were 13.1 ± 3.4 μg/liter, and IGF-I levels were 592.9 ± 53.9 μg/liter. Results after 12 months of therapy indicated reduction in GH (3.2 ± 0.7 μg/liter; P < 0.0001) and IGF-I (321.9 ± 33.9 μg/liter; P < 0.001) concentrations, and this was sustained at latest follow-up. Using GH criteria (serum GH < 2 μg/liter), 46% of subjects achieved a cure at 12 months, and 36% achieved a cure long-term. Fifty-two percent achieved normal IGF-I values at 12 months, and 67% long-term. Mean fasting and 2-h plasma glucose concentrations were similar at latest follow-up and at 12 months to baseline values. Three patients developed impaired glucose tolerance within 12 months of treatment, one going on to develop frank diabetes mellitus. However, glucose tolerance improved in five patients. Five patients developed gallstones while on treatment. In summary, this study reports the long-term efficacy of the depot somatostatin analogs as either adjuvant or primary therapy. Although overall glucose tolerance did not change, the development of impaired glucose tolerance in three patients at a time when GH levels were not changing highlights the ongoing need to monitor the long-term safety of these preparations.