OBJECTIVE: To explore the natural fluctuations in cardiovascular risk factors over a 16-week extended baseline period and to investigate the effect of a 16-week progressive resistance training intervention on cardiovascular risk factors in people living with secondary progressive multiple sclerosis. DESIGN: Secondary analysis of a single-arm non-randomized clinical trial with extended baseline. SETTING: Outpatient physiotherapy and rehabilitation clinics. PARTICIPANTS: 30 people living with secondary progressive multiple sclerosis (mean age 54 years; 67% female). INTERVENTIONS: 16-week progressive resistance training intervention (PRT). MAIN OUTCOME MEASURE(S): Systematic COronary Risk Estimation (SCORE), Framingham risk score, and individual cardiovascular risk factors (i.e. anthropometrics, blood pressure, lipids and lipoproteins, and glycemic controls markers) measured at week 0 (baseline), week 16 (extended baseline), and week 32 (post PRT). RESULTS: Despite significant improvement in muscle strength after PRT, PRT did not yield statistically significant or clinically relevant changes in any of the cardiovascular risk parameters. Natural fluctuations during the extended baseline period were small, with ICC values ranging from 0.717 to 0.983, except for systolic blood pressure (ICC: 0.471). CONCLUSIONS: Our findings indicate that a 16-week PRT program did not lead to improvements in cardiovascular risk among individuals with SPMS. The observed natural fluctuations in cardiovascular risk factors were small in this population, with overall baseline cardiovascular risk comparable to Dutch norms.