Coxiella burnetii phase I whole cell vaccine (WCV) is associated with risk of severe local delayed-type hypersensitivity (DTH) reactions in previously immunized individuals or those sensitized by natural exposure. We compared this vaccine to another investigational vaccine derived by chloroform-methanol extraction of phase I whole cells (chloroform-methanol residue vaccine, CMRV). Hairless guinea pigs, sensitized with either WCV or CMRV, were given 60,600 and 6,000 ng of WCV or CMRV in an intradermal (i.d.) skin test. The i.d. administration of WCV consistently caused more host reactions than comparable doses of CMRV in guinea pigs sensitized with either WCW or CMRV, suggesting that CMRV may be a safer vaccine. However, the CMRV was not innocuous and caused significant indurated lesions and micro-abscesses at the 600 ng and 6,000 ng skin test sites.