Several monoclonal antibodies (MAbs) to CD9, a surface membrane glycoprotein of 24 kDa found on platelets as well as several other hematopoietic and nonhematopoietic tissues, have the property of activating platelets. We have recently shown that with two of these MAbs (ALB-6 and SYB-1) this activation is mediated by interaction of the Fc portion of these IgG1 subclass MAbs with the Fc gamma II receptor (FcRII) and is blocked by a MAb to this receptor (IV-3). In this report we show that several MAbs to the CD9 antigen (BA-2, BU-16, MM2/57) also cause extensive and rapid platelet lysis in plasma. This lysis is mediated by the classical complement pathway dependent on C1q fixation. Lysis was not blocked by inhibiting platelet activation with prostaglandin E1 or by the MAb to FcRII (IV-3). The CD9 MAb BU-16 can also activate platelets through the FcRII when complement lysis is prevented by removal of C1q using specific antisera or by isolation of the platelets from plasma.