The analogs of N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP), 6-O-stearoyl-MDP (L18-MDP), and N-(N-acetylmuramyl-L-alanyl-D-isoglutaminyl)-N-stearoyl-L-lysine (MDP-Lys-L18) and N-(2-tetradecylhexadecanoyl)-MDP (B30-MDP) induced acute polyarthritis in both euthymic rats and in athymic nude rats after a single or multiple systemic administrations of their aqueous forms; water-in-oil emulsions did not induce acute polyarthritis. MDP and the adjuvant-active analogs MDP-O-nBu (MDP butyl ester), N-(3-hydroxy-2-docosylhexacosanoyl)-MDP (BH48-MDP) and the adjuvant-inactive analogs [L18-MDP (L)] or MDP-Lys-L18 (L), which is 6-O-stearoyl-N-acetylmuramyl-L-alanyl-L-isoglutamine, or N-(N-acetylmuramyl-L-alanyl-L-isoglutaminyl)-N-stearoyl-L-lysine, did not induce disease, at the dosages used. Histological examination of the acute exudative inflammatory reactions around joints revealed hypertrophy of both synovial villi and tendon sheath, infiltration of polymorphonuclear leukocytes (PMN) and fibrin deposition of the affected joint spaces. Most of these lesions rapidly subsided after cessation of the adjuvant injections. During multiple systemic injections of acyl-MDPs, this acute arthritis became chronic in euthymic rats but not in athymic nude rats; the chronic polyarthritis consisted of mononuclear cell infiltration and proliferation of the connective tissue growth and severe new bone formation of the shaft of the bone. It remains uncertain whether chronic polyarthritis results from the repeated flare of acute inflammatory reactions to the continuing stimulation of the adjuvants or whether it may require some immunologic process to such exogenous substances as bacterial fragments or autoantigens modified by exogenous substances such as type II collagen.