Lack of exon 3 of the GH receptor (d3-GHR) has been associated with increased responsiveness to GH therapy. By analogy, we hypothesized that patients with acromegaly bearing the d3-GHR genotype may have a more morbid clinical and biochemical picture. Our objective was to determine whether the GHR genotype, by modifying tissue sensitivity to GH, influences the clinical/biochemical expression of acromegaly and its outcome after treatment. The study was conducted at a specialized clinic at a tertiary care hospital. We conducted a prospective genotype investigation and retrospective analysis and correlation with clinical, biochemical, and outcome data from a group of 148 patients. Samples from 175 healthy blood donors were used as controls. GHR genotyping was performed by real-time PCR. We assessed prevalence of the three GHR genotypes (fl/fl, d3/d3, and d3/fl), associations between the genotypes, and baseline as well as post-therapeutic characteristics. Prevalence of the fl/fl, d3/d3, and d3/fl genotypes was 45, 22, and 32%, respectively, similar to what was found in the controls. Baseline characteristics were similar in carriers of the three genotypes. A positive correlation between IGF-I and log GH concentrations was significant only in homo- or heterozygous d3 carriers. Among d3-GHR carriers, diabetes, but no other comorbidities, was more prevalent (odds ratio = 2.02; 95% confidence interval = 0.96-4.2). d3-GHR carriers had significantly higher IGF-I concentrations after treatment. Multiple regression analysis revealed that the homo- or heterozygous lack of exon 3 was the strongest predictor of persistent biochemical activity (odds ratio = 1.29; 95% confidence interval = 0.65-2.58). The absence of exon 3 of the GHR may be associated with a more morbid acromegalic clinical and biochemical picture and a lower chance of achieving IGF-I normalization after therapy.