PURPOSE/HYPOTHESIS: Functional deficits and pulmonary impairments, such as muscle weakness, fatigue and impaired cough have long been recognized as major causes of morbidity and mortality in individuals with advanced MS. This study examined the effect of a 10-week home-based inspiratory muscle threshold trainer exercise program (IMT) on four physical performance tests in persons with MS. NUMBER OF SUBJECTS: Forty-six ambulatory individuals (8 male & 38 female) diagnosed with MS participated in this study. Age ranged from 35-69 years old, mean (X)=50.0 in the experimental group (E) and from 23-64 years old (X=46.2) in the control group (C). Expanded Disability Status Scale scores for subjects ranged from 2.0-6.5 for both groups with X=3.96 for E and X=3.36 for C. Type of MS was: relapsing remitting (E=10, C=16), secondary progressive (E=3, C=4), primary progressive (E=4, C=1), progressive relapsing (E=2, C=1), unknown (E=4, C=1). MATERIALS/METHODS: An experimental, randomized, control design. The Six-Minute Walk Test (6MWT), Functional Stair Test (FST), and Sit-to-Stand Test (SST) were direct measures of gross motor function used in daily life. The FST and SST require anti-gravity lower extremity muscular strength and power to complete the test. The single limb Romberg (RMB) was included since balance affects many functional tasks. The home pulmonary training program performed with a Threshold Inspiratory Muscle Trainer device set at an initial resistance of the 30% PI Max consisted of 3 sets of 15 repetitions daily for 10 weeks and was progressed weekly by increasing resistance based on RPE with additional repetitions and sets added when the resistance could no longer be increased. Statistical Analysis (significance, p 0.05): a) Independent, one-tailed t-test between E and C groups of PI Max improvements, b) Wilcoxon Signed Rank tests on pre- to post-test change for the other dependent variables, and c) Pearson Product-Moment Correlations to examine relationships between variables for inclusion in multiple stepwise regression model. Regression analysis on the 6MWT were run with many potential co-vari-ables including: FST, SST, RMB, age, wt., ht., MS type, EDSS score, muscle tone and strength, and Fatigue Severity Scale score. RESULTS: PI Max increased significantly after training for E compared to C (p=.000, range 100%-400%) as did 6MWT (p=.017) and RMB (p=.007). Compliance with IMT Protocol averaged 81% (range=76.25%-83.50%). The E group average percent improvemnt was 3.1% in 6MWT distance and 5.6% on RMB time. FST and RMB were included in the final regression model for 6MWT. 73% and 76% of variance of 6MWT distance before and after IMT, respectively, was explained by FST alone. When both FST and RMB were modeled, 77% and 80%, respectively of variance was explained. CONCLUSIONS: IMT significantly increased 6-MWT distance and increased time for maintaining balance on the one-legged RMB Test in persons with MS. CLINICAL RELEVANCE: IMT may augment traditional physical therapy treatment to improve endurance and balance in ambulatory persons with MS.