We present evidence that homogeneous submicron particles can influence the growth rate of larger particles upon long‐term storage in a temperature‐dependent manner. Interferon‐beta‐1a was thermally stressed at 50°C for 6 h and characterized using nanoparticle tracking analysis (NTA), microflow digital imaging (MFI), and circular dichroism (CD) spectroscopy. This study showed selective formation of submicron particles exhibiting a perturbed protein conformation. These thermally induced submicron particles were spiked into an unstressed solution at three levels, and then monitored for micron‐sized particle formation upon storage at 5°C and 25°C for 12 months. The resulting particle growth effects were temperature dependent. NTA and MFI results at 5°C showed little evidence that initial submicron particle levels impacted particle growth across the range ∼0.03–25 μm. In contrast, MFI results at 25°C indicated that particle growth in the 1–10 μm size range correlated strongly with initial submicron particle levels, and particle counts in the 10–25 μm size range were highest after 12 months for the samples with highest initial submicron particle content. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:347–351, 2013