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Nicki Aycox lived a full artistic life since the age of nine, when she fell in love with the family piano and began playing music. By the time she had reached her preteens Nicki was performing Beethoven for audiences all around Oklahoma, until her family had a huge financial setback and was forced to sell her piano. Nicki said that this sad circumstance played a major role in her shift to the theater. Like a lot of kids her age she began performing in her high school theater, and also in drama competitions. She won state titles in different categories, and became very comfortable with being in front of an audience. She once said that she was on stage long before she ever actually sat in an audience. After high school graduation she attended the University of Oklahoma and began serious academic study. Soon, however, she found herself driving to California to enroll in the theater department at Long Beach State. While working two jobs and participating in the theater department, Nicki found little time to study and take a full class load. In her second year at Long Beach State Nicki was able to sign with a small agency in Hollywood, and thus began her career as a professional performer - a career which began relatively quickly compared to most. She was working small bit parts on several popular networks and shows within a year of making the move from Oklahoma to Los Angeles. In the beginning of her career Nicki acted opposite actor Stephen Rae in an HBO film called "Double Tap", as well as appearing in shows like "Third Rock from the Sun", NBC's "Providence", David Kelley's "Ally McBeal", and in the X-Files episode "Rush" in 1999. That role from the TV show led to a role in the second "X-Files" film "I Want to Believe" in 2008. In a time when an unspoken difference between "film" actors and "television" actors existed, Aycox did not allow this rule to apply to her.

Her work during these early years included guest spots on "CSI", and "Dark Angel", a recurring role n NBC's "ED" playing the wild and crazy sister of Julie Bowen. At some points Nicki would be pulling double duty playing roles on different shows. She played the sister of Katherine Morris on CBS's "Cold Case", while shooting the series "LAX" with Heather Locklear. By 2005, Aycox was made a series regular on shows such as FX's "Over There" created by Steven Bochco and Chris Gerolmo. She moved on from there to play a very memorable role as a psychotic serial killer in an episode of "Criminal Minds" titled "The Perfect Storm". The following year Nicki appeared in the Halle Berry film "Perfect Stranger". One of her most widely known roles was that of Meg Masters in "Supernatural".

In the years 2009-2013 Aycox enjoyed success as a series regular as Jamie Allen in the Bruckheimer series "Dark Blue". Next she was cast as Lisa Matthews in the Indie film "Lifted", directed by Oscar nominated director Lexi Alexander. Around this time she also awarded a best actress award by the Buffalo Niagara film festival for her portrayal as a German woman fighting to save her sanity in the World War II film "Christina". Her co-star, Stephen Lang, was also awarded for his role as Inspector Reinheart. Aycox spent her final years reclaiming her love of music, playing the guitar and singing for audiences, as well as continuing her acting career.

Aycox revealed on Instagram that she had been diagnosed with leukemia in March 2021. She passed away on November 16th, 2022.