Coccidioidin, an extract from the saprophytic mycelial form of Coccidioides immitis, has been a very useful antigen preparation in serological tests for coccidioidomycosis. Its sensitivity has been very good for detecting most types of clinical disease, but tests with coccidioidin have been negative for 40% or more of patients with chronic pulmonary disease, the clinical entity which must be differentiated from other cavitary, nodular, or fibrotic pulmonary disease, e.g., tuberculosis and cancer. The specificity of coccidioidin has also been good although it results in positive tests for an average of 16% among patients with noncoccidioidal mycoses. Recently spherulin, an extract from the parasitic endosporulating spherule form of C. immitis, was reported to be more sensitive than coccidioidin in concurrent complement fixation tests with sera from selected cases. We have compared coccidioidin and spherulin in concurrent complement fixation tests with 614 sera submitted routinely for coccidioidal serology and with 159 selected sera from patients with noncoccidioidal mycoses. Among the former, spherulin was positive with 25% and coccidioidin with 23%, and correlation of titer scores was highly significant. Statistical analysis revealed no significant differences with respect to frequency of positive specimens, titer scores, or diagnosis for current coccidioidomycosis. The results with sera from noncoccidioidal mycoses revealed marked differences. Coccidioidin was positive with 20%, and spherulin was positive with 48%. The titer scores with spherulin were consistently and significantly higher, and there was no correlation for results with the two antigens. Thus, coccidioidin and spherulin were equally sensitive, but spherulin was considerably less specific.