The fate of Chlamydia trachomatis (L2/434/Bu) in human peripheral blood monocytes and human monocyte-derived macrophages was studied by transmission electron microscopy (TEM) and by measuring the yield of infectious C. trachomatis in one-step growth experiments. Two main types of phagosome were seen by TEM in the cytoplasm of C. trachomatis-infected human monocytes (1 h postinfection [p.i.]): one in which the elementary body (EB) was tightly surrounded by the membrane of the phagosome and another in which the EB appeared in an enlarged phagosome. Later, 24 to 48 h p.i., each phagosome contained a single EB-like particle, an atypical reticulate body, or a damaged particle. One-step growth experiments showed that infection of human monocytes with C. trachomatis results in a decrease of infectious particles between 24 and 96 h p.i., whereas infection of the monocytes by C. psittaci (6BC strain) results in productive infection with, however, a 3.5-log lower yield than in control MA-104 cells. In contrast to the abortive replication of C. trachomatis in monocytes, monocyte-derived macrophages permitted replication as indicated by one-step growth experiments and TEM. in C. trachomatis-infected, monocyte-derived macrophages 72 h p.i., inclusions of two kinds were observed by TEM. One was very similar to the typical inclusions appearing in infected MA-104 (control) cells; the other was atypical, pleomorphic, often contained "channels," and held relatively few EB and reticulate bodies, some of which appeared damaged or abnormal. The significance of the responses to infection with C. trachomatis in monocytes compared with monocyte-derived macrophages and the role of these cells in sustaining chronic or latent infection and in dissemination of the infection to various parts of the body is discussed.