Malignant ascites is a common phenomenon in cancer patients. It poses a great challenge to the clinician, because of limited treatment options and strong impairment of the quality of life of the often palliative patients. The SECIMAS study investigated the feasibility of a re-challenge with four catumaxomab intraperitoneal infusions in patients who had already received a first cycle of four infusions in the phase III CASIMAS study, which compared catumaxomab with and without prednisolone premedication. The primary endpoint was the proportion of patients who received at least three catumaxomab infusions. Secondary endpoints included a composite safety score (CSS) summarising the worst grades for the main catumaxomab-related adverse events (pyrexia, nausea, vomiting and abdominal pain), safety, efficacy and the occurrence of anti-drug antibodies (ADAs). Eight of nine screened patients received a second catumaxomab cycle. Compliance with a catumaxomab re-challenge was high: all eight patients (100%) received all four infusions. The median CSS was 3.0 versus 3.4 in CASIMAS. The tolerability profile of the second catumaxomab cycle was comparable to that of the first cycle. Median puncture-free survival (48 days) and overall survival (407 days) were longer than in CASIMAS (35 and 103 days, respectively), although median time to next puncture was shorter (60 vs. 97 days). Of six patients sampled, all were ADA positive at screening and remained ADA positive until the end of the study. The presence of ADAs did not affect catumaxomab's safety or efficacy. The CSS and tolerability profile for catumaxomab in SECIMAS were comparable to those in CASIMAS. The majority of patients benefitted from a second cycle of catumaxomab. A re-challenge seems to be feasible and safe for selected patients with recurrent malignant ascites due to carcinoma after a first cycle of catumaxomab.