Objective. To analyze the safety of our biopsy technique and the effectiveness of minor salivary gland biopsy (MSGB) for the diagnosis of Sjö gren's syndrome (SS) and amyloidosis. Methods. We conducted a retrospective analysis of 452 patients with suspected SS and 50 with suspected amyloidosis and negative periumbilical fat aspiration analysis who underwent MSGB at a single center. Diagnostic evaluation for SS included Schirmer's test, unstimulated whole salivary flow, detection of antinuclear antibodies and anti-SSA/SSB, erythrocyte sedimentation rate, C-reactive protein, IgM rheumatoid factor, and serology for hepatitis C virus. For all biopsy samples, a cumulative focus score on multilevel sections was calculated. SS was diagnosed according to American-European Consensus Group (AECG) criteria. Histologic evaluation for amyloidosis was performed using Congo red staining and polarized-light microscopy. Adverse events were recorded on a questionnaire immediately after the procedure and 7 days, 14 days, and 6 months thereafter. Results. Sixty-four patients (12.7%) reported transient adverse events: 40 paresthesias lasting <7 days, 17 paresthesias lasting <14 days, 27 cases of local swelling, and 8 external hematoma. One patient has had local paresthesia for 2 years. A total of 498 (99.2%) samples provided adequate material for histologic analysis. Of 452 patients evaluated for SS, 378 were finally evaluated. Ninety-three patients (24.5%) had a cumulative focus score >1, and 87 (94.5%) of 93 satisfied the AECG criteria. Classification of SS was possible for 124 (32.8%) of 378 patients. In 51 (41%) of 124, MSGB was essential to reach the number of criteria needed for classification. Of 50 patients evaluated for amyloidosis, 10 (20%) had positive Congo red staining. Conclusion. MSGB is a simple, safe, and reliable tool for the diagnosis of SS and amyloidosis, and therefore is suitable for more extensive application.