Institutions of higher education, states, and local K–12 districts have been challenged to improve math and science education for our nation's students. In the past few years, there has been renewed interest in inquiry-based, activity-oriented instruction in science for students with disabilities. Yet, there still exists the need for further empirical evidence to support instructional improvements for students with more involved emotional and behavioral disabilities. This study describes a program in which 18 middle school students with serious emotional disturbances were instructed, over the course of 8 weeks, on “Matter” by two different instructional approaches. Students in one classroom received a traditional textbook approach to science content, whereas students in another classroom received science instruction by a hands-on, thematic approach. Over the course of instruction, data were collected regarding students' behavior and achievement. Results indicate that, overall, students in the hands-on instructional program performed significantly better than the students in the textbook program on two of three measures of science achievement, a hands-on assessment and a short-answer test. The students did not differ on a multiple-choice format test. With regard to behavior, there were no significant differences in behavioral problems found between the two groups of students over the course of the study. Findings are discussed in relation to instructional implications for students with disabilities in the science classroom. © 2005 Wiley Periodicals, Inc. J Res Sci Teach 42: 245–263, 2005