This study is aimed at investigating the relationships among students' relevant prior knowledge, meaningful learning orientation, reasoning ability, self-efficacy, locus of control, attitudes toward biology and achievement with the human circulatory system (HCS) using the learning cycle (LC) and the traditional classroom setting. The study was conducted with two teachers and four classes for a total of 60 11th grade students from high school. One class for each teacher was assigned as an experimental group and treated with 5E LC instruction and the other class was assigned as a control group and treated with traditional instruction (TI). The Human Circulatory System Achievement Test (HCSACT) was administered twice as a pre-test and after the treatment period, as a post-test to both the experimental and control groups. The Learning Approach Questionnaire, Test of Logical Thinking, Self-Efficacy Scale, Locus of Control Scale and Attitude toward Biology Scale were also administered to all students. The results indicated that the LC improved students' achievement in the HCSACT compared to TI. Stepwise multiple regression analysis revealed that in the learning cycle classrooms, the main predictors of achievement on the HCSACT were students' reasoning ability (45.8%) and their prior knowledge (15.9%). In traditional classrooms, students' meaningful learning orientation (40%) and locus of control (9.8%) were the main predictors of achievement.