The influences of in vivo pretreatment with phenobarbitone (PB), 3‐methylcholanthrene (3‐MC), 2,2’,4,4’,5,5'‐hexachlorobiphenyl (HCBP), and 3,3’,4,4'‐tetrachlorobiphenyl (TCBP) on cytocidal hepatotoxicity of two pyrrolizidine alkaloids, lasiocarpine (LC) and senecionine (SC), were compared in short‐term primary cultures of rat hepatocytes. Toxicity was measured by release of lactate dehydrogenase (LDH) into culture medium at 24 h. LC was slightly more toxic to control hepatocytes than SC in the graded response range of 10–160 μM. PB and HCBP (a PB‐type polychlorobiphenyl inducer) similarly potentiated toxicity of SC, and each diminished the degree to which cell killing by LC and SC was inhibited by SKF‐525‐A. By comparison, 3‐MC and TCBP (a 3‐MC‐type PCB inducer) each diminished toxicity of SC but had little effect on toxicity of LC. Alpha‐naphthoflavone (ANF) potentiated toxicity of both LC and SC in hepatocytes induced by 3‐MC or TCBP but had little effect on responses of hepatocytes induced by either PB or HDBP. These results indicate that xenobiotics that induce similar patterns of cytochrome P‐450 isozymes have qualitatively similar modulating influences on cytocidal hepatotoxicity of pyrrolizidine alkaloids in primary cultures. However, the observed modulating effects could not be explained solely on the basis of altered activation rates by the cytochrome P‐450 species known to be induced by the various xenobiotics.