Distal obstruction of the lymphatics by tumor and extensive tumor infiltration of the draining lymph nodes may prevent migration of the tracer to the sentinel lymph node (SLN), adversely affecting SLN identification. Rerouting of lymphatic drainage may divert flow to internal mammary nodes and cause an alternative nonsentinel node to become "sentinel," increasing the risk of a false-negative result. A total of 618 breast cancer patients underwent SLN biopsy using 99mTc albumin colloid and patent blue V injected peritumorally. This was followed by standard axillary node clearance in all patients at the same operation. The overall SLN identification and false-negative rates were 96% (593/618) and 7.6% (17/223), respectively. There was no difference in the SLN identification rate and the false-negative rate with increasing axillary tumor burden (as determined by the total number of positive nodes in the axilla). Further detailed analyses are based on the 64 patients from one center (Cardiff) who had at least one positive SLN and proceeded to axillary clearance. A total of 83 positive SLNs were removed from 64 patients. Tumor burden in the positive SLN was assessed by measuring the size of the metastasis and percentage replacement of the SLN by tumor, and by documenting extranodal invasion. Increasing tumor burden in the SLN (as determined by percentage replacement of SLN by tumor and presence of extranodal invasion) was associated with decreased radioisotope uptake (p = 0.005 and p < 0.0001, respectively). There was no correlation between radioisotope uptake and the size of the metastasis in the SLN. There was no correlation between blue dye uptake, internal mammary drainage on lymphoscintiscan, and tumor burden in the positive SLN. In conclusion, increased axillary lymphatic tumor burden is not associated with failure to identify a SLN or false-negative results when both blue dye and radioisotope are used for SLN biopsy. In an individual SLN, the percentage replacement by tumor, but not the absolute size of the metastatic deposit is associated with reduced radioisotope uptake. Extranodal invasion in the SLN is a marker of lymphatic obstruction and is significantly associated with reduced radioisotope uptake. The lymphatic tumor burden does not seem to affect blue dye uptake or internal mammary drainage.