Minimally invasive adrenalectomy (MIA) is both feasible and safe with either transperitoneal or retroperitoneal entry. However, only a few studies have rigorously compared these two techniques. The aim of the current study is to compare transperitoneal and retroperitoneal adrenalectomy to detect significant differences in patient selection and perioperative outcomes. Between 1995 and 2009, 171 patients underwent MIA through transperitoneal (n = 127) or retroperitoneal access (n = 44). The respective cohorts were then examined retrospectively through matched and unmatched comparisons. Multivariate analyses of intraoperative blood loss, postoperative morbidity, and length of hospital stay were performed. Surgical indications were benign lesions (70.2%), malignant tumors (11.1%), and pheochromocytomas (18.7%). The postoperative morbidity rate was 15.8 per cent, but mortality was null. The rate of conversion to open surgery was 5.3 per cent. Blood loss and operative time were significantly lower with the transperitoneal approach, whereas time to oral intake was shorter for the retroperitoneal group. Tumor size less than 4.5 cm was associated with less blood loss, shorter hospital stay, and lower postoperative morbidity. Laparoscopic and retroperitoneal routes are both effective and safe for excising adrenal lesions. In the present study, however, laparoscopic adrenalectomy demonstrated shorter operative times with less blood loss. Regardless of this, we remain cautious in recommending one procedure preferentially. Other important measures of clinical outcome such as required pain control, ease of patient recovery, and cost considerations were not included in this analysis. Further randomized trials, with large patient numbers, are therefore desirable for defining an optimal surgical method.