AbstractComplex segregation analysis under the unified mixed model of inheritance (major gene and multifactorial) is performed on families ascertained through 23 probands with hypoalphalipoproteinemia (depressed HDL‐cholesterol, denoted HDL‐c). Evidence for segregation of a recessive major gene for depressed HDL‐c with frequency q = 0.116, in addition to multifactorial transmission (H = 0.572), is found in these families. Reanalysis of a subset of families with severely depressed HDL‐c confirms the conclusions based on the original analysis, except that different definitions of “affection” give rise to different estimates of gene frequency. Our finding of a recessive mode of inheritance differs from previous claims for a dominant gene because previous analyses did not use a mixed model for segregation analysis of hypoalphalipoproteinemia. When the significant multifactorial background is neglected, we also find evidence for the invalid claim of a dominant gene. This demonstrates the necessity of using mixed models for determining the mode of inheritance of a give