Complement plays an important role in the immune attack against invading microorganisms. However, blood-contacting medical device biomaterials lacking specific complement inhibitors, with free hydroxyl and/or amino groups, or with absorbed antibodies, may inappropriately activate complement. Inappropriate activation by either the antibody-mediated classical or the antibody-independent alternative pathway may have well-known acute or poorly understood chronic effects on the host or device. This article describes methods for screening biomaterials for functional whole complement activation using normal human serum, or specifically for alternative pathway activation using C4-deficient guinea pig serum, or for classical pathway activation using both sera in combination. Detailed protocols are available as standard methodologies from the American Society for Testing and Materials (ASTM F1984, ASTM F2065, and ASTM F2567). Results obtained with these functional tests are confirmed by detection of classical and alternative pathway-specific markers C4d and Bb, respectively. These methods demonstrate dose and time-course activation of complement to beaded agarose, cellulose acetate, and purified alginate as examples of biomaterials. Significant difference in a functional endpoint denoting specific complement pathways is an appropriate screening method for complement activation by medical device biomaterials which might result in adverse events when the device is implanted or contacts human blood.