Two experiments were conducted to examine the responses of weaned pigs to inoculation with tachyzoites of the temperature-sensitive mutant (TS-4) of Toxoplasma gondii. Experiment 1 was done to examine the safety of the TS-4 mutant in weaned pigs given a single inoculation. No clinical sign was observed in 2 pigs inoculated subcutaneously (s.c.) (group 1) or 4 pigs inoculated intravenously (group 2) with 5 x 10(5) tachyzoites. No lesion was observed in the tissues of pigs in group 1; 3 of 4 pigs in group 2 had focal areas of gliosis and lymphocytic perivascular infiltrates in their brains. One pig also had focal areas of lymphocytic infiltrates in hepatic portal triads. No stage of T. gondii was observed in the tissues of these pigs. The TS-4 mutant was not isolated in mouse bioassay from the tissues of the 6 pigs in experiment 1. Experiment 2 was done to determine if 2 inoculations s.c. with TS-4 tachyzoites would protect pigs against inoculation orally with T. gondii oocysts. Pigs were inoculated s.c. with 5 x 10(5) TS-4 tachyzoites (4 pigs, group 3) or Hanks' balanced salt solution (4 pigs, group 4) on days 0 and 14 postinoculation (PI) and orally challenged with 1 x 10(5) oocysts of the GT-1 isolate of T. gondii 30 days Pl. Clinical response to oocyst inoculation was more severe in pigs in group 4. Rectal temperatures of pigs in group 3 were significantly (P < 0.05) lower than pigs in group 4 on days 3, 4, and 9 following inoculation with oocysts. Mild lesions of focal gliosis and perivascular lymphocytic infiltration were observed in the brains of 2 pigs in group 3 and 3 pigs in group 4. A single T. gondii tissue cyst was observed in the brain of a pig in group 4, microscopic examination of tissues from all other pigs was negative for T. gondii. Bioassay demonstrated that T. gondii tissue cysts were present in the tissues of all pigs in groups 3 and 4.