To identify predictive factors of response to interferon alpha (IFN-alpha) plus ribavirin therapy in patients with chronic hepatitis C (CHC), the presence of lymphadenopathy (LyA) of the hepatoduodenal ligament and other variables were investigated. A total of 110 patients with histologically proven CHC were enrolled in this study. Ultrasound (US) was performed at the start and end of therapy and 6 months after stopping therapy. At baseline, LyA was present in 35 (43.7%) of 80 patients with alanine aminotransferase (ALT) values and grading was significantly higher than in the LyA-negative group. LyA was more frequent in nonresponders (nonR) than in relapsers (relR) or sustained responders (susR). Lymph node volume (LyV) was significantly lower in susR than in nonR or relR (p < 0.05). Under antiviral treatment, the reduction in LyV was significantly higher in nonR (p < 0.01); in susR and relR, it was not significantly reduced. LyA totally disappeared in two patients of the susR group. Logistic regression analysis confirmed only a positive association of susR with grading and a negative association with staging (p < 0.02 and p < 0.006). In conclusion, this study suggests that US evidence of LyA is useful in evaluating the severity of a given chronic hepatitis C, but it cannot be proposed as a predictive index of response to antiviral treatment.