Based on the symmetry of transmitted/nontransmitted alleles from heterozygous parents under the null hypothesis of no association, the work proposed here establishes a general statistical framework for constructing association tests with data from nuclear families with multiple affected children. A class of association tests is proposed for both diallelic and multiallelic markers. The proposed test statistics reduce to the transmission disequilibrium test for trios, to Tsu by Martin et al.([1997] Am. J. Hum. Genet. 61: 439–448) for affected sib pairs, and to the pedigree disequilibrium test by Martin et al.([2000] Am. J. Hum. Genet. 67: 146–154);[2001] Am. J. Hum. Genet. 68: 1065–1067) when using affected sibships only. The association test used in simulation and for real data (sitosterolemia) is the one which has the best overall power in detecting association. This association test is generally more powerful than the association tests proposed by Martin et al.([2000] Am. J. Hum. Genet. 67: 146–154);[2001] Am. J. Hum. Genet. 68: 1065–1067) when using only affected sibships. For the sitosterolemia data set, the association test has its most significant result (P-value¼0. 0012) for the marker locus on the same bacterial artificial chromosome as the disease locus. Genet Epidemiol 24: 208–219, 2003. & 2003 Wiley-Liss, Inc.