Background. In IWCLL guidelines, progressive splenomegaly and lymphadenopathy are signs of active disease. In this study, we have tested the hypotheses if US could be a reliable tool for both superficial lymphnodes (SupLNs) and splenic assessment in chronic lymphocytic leukemia (CLL) patients. Methods. We enrolled N = 75 patients. SupLN and the spleen were assessed by two independent physicians (M1 and M2) by palpation and by a third physician (M3) with ultrasound sonography (US) using two different sonographers (US1 and US2). The results of M1 vs. M2 assessment, US1 vs. US2, palpation vs. US were compared. The echostructure of N = 1037 SupLN and of the spleen was also investigated. Results. The dimensions of SupLNs assessed by MD1 vs. MD2 were statistically discordant. Splenic size was concordant. There was concordance between US1 and US2 SupLN and splenic assessment. US found a higher number of pathological SupLN (Cohen’s Kappa < 0.1) than palpation, which misses remarkable-sized SupLNs. LN echostructure and splenic involvement patterns were described. Conclusions. US is a reliable, radiation-free tool useful in clinical practice to assess SupLN and splenic involvement in CLL.