No studies have focused on the relationships between pathological changes in the subsynovial connective tissue and clinical or neurophysiological findings in patients suffering from carpal tunnel syndrome (CTS). Twenty-five consecutive patients (mean age 58.8±10 years; range 39–79) operated on for idiopathic CTS were evaluated before surgery and six month later. The indication for surgery was the presence of symptoms despite a three-month trial of conservative management. Mean duration of symptoms was 5.3±4.6 years (range 0.5–15). On admission, demographic and medical history data were recorded from all the patients. Subsequently, patients underwent preoperative physical examination and an outcome set including a mixed historic and objective scale (Hi-Ob), the Italian version of the Boston Carpal Tunnel Questionnaire (BCTQ) and the official Italian version of the SF-36 questionnaire was administered. The baseline diagnostic work-up included standard radiographs of the hand and wrist, blood examination and neurophysiological testing. Patients underwent open carpal tunnel release and thickened synovium from the flexor digitorum superficialis tendons was harvested. The number of cells, the number, diameter and density of the vessels, and the total surface of angiogenetic foci were measured. On the SF-36 questionnaire, the preoperative physical component summary (PCS) and mental component summary (MCS) scores averaged 36.5±4.2 and 40.8±5.7, respectively; at follow they averaged 47±10.2 and 46.8±7.3, respectively, with significant improvement for PCS. Preoperative and postoperative Hi-Ob scores measured 3.4±0.5 and 1.3±0.5, respectively. The BCTQ symptoms scale averaged 3.9±0.3 before surgery and 1.5±0.2 at follow up, whereas the BCQT functional status scale measured 3.4±0.5 at baseline and 1.4±0.3 six months after the operation. Univariate and multiple linear regression analysis were used to evaluate relationships between explanatory variables and outcomes. A high grade of preoperative neurophysiologic impairment was in direct relationship with the improvement in SF-36’s PCS score obtained with surgery (p=0.017). Conversely, no association was detected between neurophysiological grade and the postoperative improvement in Hi-Ob or BCQT scales. The univariate analysis showed a trend toward a direct association between number of vessels in the synovium and the improvement of BCTQ symptoms at follow-up (p=0.06). This trend was confirmed to a lesser extent at the multivariate analysis. With the numbers available, no other histological parameters were associated with the baseline neurophysiological findings or clinical outcomes. Although our results should be interpreted cautiously due to the small sample size, we conclude that the severity of pathological changes in the flexor synovium during CTS do not influence the baseline severity or outcome of this syndrome.