He is known for his work in mental health statistics, particularly assessing the reliability of diagnostic classifications, and the measures, models, and control of errors in categorization.

[2] In 1975, Columbia University recruited Fleiss to be a professor and head of the Division of Biostatistics at the School of Public Health.

Fleiss transformed the Division from a small program consisting chiefly of New Yorkers into a department with international prestige.

[2][3][4] One of Fleiss's chief concerns was mental health statistics, particularly assessing the reliability of diagnostic classifications, and the measures, models, and control of errors in categorization.

According to professors Patrick E. Shrout and Melissa D. Begg, the book "attracted a wide readership with its many engaging examples and a thorough, but accessible discussion of esoteric statistical principles".

[2][4] Fleiss's second book, Design and Analysis of Clinical Experiments (1986), was equally influential among a different group of medical researchers.

Human subjects present experimenters with challenges not seen in other scientific experiments: they may fail to take the treatment, they may drop out of a study, and they may lie or misrepresent the outcome.

[2][4] Because of the high reputation he enjoyed in the field of biostatistics, Fleiss was asked to participate in a large number of scientific panels and review groups for the U.S. Food and Drug Administration and the National Institutes of Health.