Purpose: To evaluate the sensitivity, specificity, advantages, and limitations of multiplex ligation-dependent probe amplification compared with conventional karyotype analysis in the investigation of contributing factors to recurrent pregnancy loss. Method: A cohort of 284 patients underwent side-by-side analysis of products of conception by both conventional karyotyping and multiplex ligation-dependent probe amplification with direct comparison of results. Results: Multiplex ligation-dependent probe amplification was shown to enable a diagnosis for an additional 47 (16.5%) patients compared with conventional karyotype analysis. However, this advantage was offset by some disadvantages of the method, including a high false-positive rate (8/104; 7.7%), as demonstrated by single-arm probe abnormalities of uncertain clinical significance, as well as the inability to characterize structural rearrangements, such as Robertsonian translocations, which comprised 2.46% of samples (99% confidence interval ϭ 0.09 -4.83), and ploidy changes. The calculated performance characteristics of multiplex ligation-dependent probe amplification in this cohort yielded a sensitivity of 86.9% and specificity of 92.4%. Conclusions: The advantages of now widely accepted molecular methodologies, such as lower failure rates, faster turnaround times, and lower cost, must be complemented by adequate counseling, family follow-up, and specific diagnostic reporting practices. It is particularly important to specifically address the important limitations of the methodology, including the inability to characterize balanced structural rearrangements and ploidy changes, especially if multiplex ligation-dependent probe amplification is to be performed alone. Genet Med 2011:13(1):46 -51. Key Words: recurrent pregnancy loss, products of conception, genetic diagnosis, cytogenetics, multiplex ligation-dependant probe amplificationA proximately 15-20% of recognized pregnancies end in a spontaneous abortion before 20 weeks gestation. The burden of pregnancy loss is, however, not uniformly distributed. As a result of the increase in the risk of trisomic pregnancies with advancing maternal age, Ͼ40% of pregnancies in women older than 40 years end in spontaneous abortion. Recurrent pregnancy loss (RPL) is also frequent, affecting approximately 5% of couples. The major factors contributing to pregnancy loss are chromosomal in origin with approximately 50% of products of conception (POC) demonstrating either aneuploid or polyploid karyotypes. 1,2