Sonographic guidance is commonly used in the biopsy of focal hepatic lesions, but biopsy for diffuse disease is often non-image-guided. We evaluated the safety and efficacy of real-time sonographically guided random core biopsy in the assessment of diffuse liver disease in 210 patients. The two most common indications for biopsy were viral hepatitis (in 113 patients) and elevated liver function test results of unknown cause (in 54 patients). Ultrasonography and pathology reports were reviewed retrospectively to determine number of needle passes and final diagnoses. Adequate tissue was obtained in all 210 patients, with 259 of 269 (96%) passes having been successful. Specimens were submitted for light microscopy and other tests as indicated. No difference in success rates was found for right and left lobe biopsies. No major complications occurred. Minor complications occurred in 10 of 210 (4.8%) patients and were self-limited. Sonographically guided core liver biopsy is a safe and effective method for the diagnosis of liver disease.