The optimal processing for the pathology of sentinel lymph nodes of patients with melanoma is still a matter of debate. We compared two protocols of sentinel lymph node processing, which were consecutively applied. For the first protocol, the sentinel lymph nodes were cut into 1-2 mm thick slices. From each slice, 12 microtome sections were stained (multiple slices protocol). For the second protocol, which is a modification of the recent European Organisation for Research and Treatment of Cancer protocol, the sentinel lymph nodes were bivalved. Five consecutive series of microtome sections, with gaps of 50 microm between them, were prepared from each cut surface (bivalving protocol). H&E and immunohistochemical staining were integral elements of both protocols. A total of 584 sentinel lymph nodes (1.8+/-0.9 per patient) were examined. The percentages of micrometastases (29 versus 27%) and of capsular naevi (13 versus 15%) detected were very similar for both protocols. As shown by multivariate logistic regression, Breslow thickness (P=0.003) and younger age (P=0.01) correlated with nodal metastasis. The type of histological preparation, ulceration and sex were not significant. The multiple slices protocol produced, on average, 4 paraffin blocks and 46 microtome sections per node. The bivalving protocol constantly produced 2 paraffin blocks and 42 microtome sections. For technical processing, the multiple slices protocol required, on average, 38 min per sentinel lymph node, whereas the bivalving protocol required 55 min. Both protocols yielded excellent detection rates with a similar amount of work being required on the part of the pathologist. Compared with the bivalving protocol, the multiple slices protocol was less labor intensive for the technical staff.