Elevated levels of the extracellular domain of HER-2/neu in serum (sHER-2/neu) have been shown to be of prognostic importance. In this phase II study with weekly paclitaxel in metastatic breast cancer, we investigated the predictive quality of this serum oncoprotein by correlating the outcome of therapy to sHER-2/neu levels. Paclitaxel (90 mg/m2 weekly x6, q9w) was administered to 35 patients with complete outcome assessment and biochemical follow-up. sHER-2/neu was measured using standardized enzyme-linked immunoassays. We found that 62.9% (22/35) of the patients had elevated levels (> or = 15 ng/ml) of sHER-2/neu. The overall response rate (RR) to weekly paclitaxel was 40.0% (14/35). There was no difference in RR between sHER-2/neu-positive patients (40.9%) and sHER-2/neu-negative patients (38.5%; p = 0.4). The progression-free interval was longer for sHER-2/neu-negative patients (53.2 weeks) in comparison to sHER-2/neu-positive patients (31.2 weeks; p = 0.098). Responses were significantly more durable in sHER-2/neu-negative patients (65.2 weeks) than in the sHER-2/neu-positive subgroup (25.7 weeks; p = 0.042). Introducing hypothetical cut-offs into the sHER-2/neu-positive subset, we found that in patients with a sHER-2/neu level of greater than 22 ng/ml, the progression-free survival decreased significantly with increasing sHER-2/neu levels (p < or = 0.022). Considering the high impact of progression-free survival and duration of response as outcome parameters, the sHER-2/neu status is a predictive indicator for benefit from paclitaxel chemotherapy.