Ashok (Saif Ali Khan) and Kumar (Ritesh Deshmukh) are best friends, where as Shanaya (Tamannaah Bhatia) and Mishti (Bipasha Basu) are their love interests. Ashok's father is a multi millionaire but is in a coma for the last six years, while his wicked Mamaji (Ram Kapoor) teams up with an evil Doctor Dr. Khan (Nawab Shah) to get rid of Ashok and take over all his property.
During a board meeting Mamaji mixes a medicine in Ashok and Kumar's drink and they both start behaving like dogs. They are taken to a mental asylum for treatment by Dr. Shivani (Esha Gupta) who soon realizes the truth and promises to discharge them.
However, in a dramatic twist of fate, two look-alikes of Ashok and Kumar being treated in the same hospital's 'B' ward (who work for Bijlani (Chunkey Pandey), a cocaine smuggler) are accidentally released instead of the true ones. Shanaya and Mishti take them to Ashok's mansion were Mamaji understands the whole mix-up and plans to use the duplicate Ashok to become the owner of the whole business empire. Now the true Ashok and Kumar also come to know of Mamaji's evil plan but are stuck in the asylum.
They are offered help by one of the ward boy (Darshan Jariwala), who takes them to a secret ward 'C' to meet 'Jhonny' who is a look alike of Mamaji but has a dangerous habit of attacking people who sneeze in front of him. Ashok and Kumar plan revenge against Mamaji with the help of Johnny but get caught by the warden Y. M. Raj (Satish Shah) before they can escape from the asylum. Y. M. Raj prepares to punish them but accidentally sneezes in front of them. Angered by this, Johnny beats him black and blue, thus helping the three to escape.
On the day of the board meeting, the true Ashok and Kumar were about to expose Mamaji, when Dr. Khan triggers the fire alarm. All the three mental patients escape the building. Now, the desperate Ashok and Kumar bump into a dance bar owner Rajvinder, the triplicate of Mamaji, while Mamaji also arranges another set of Ashok and Kumar with the help of plastic surgery. Mamaji takes the triplicate Ashok and Kumar to 'House of Commons' where the fake Ashok is to hand over all the business to him in the presence of Prince Charles but the real Ashok and Kumar arrive along with the triplicate of Mamaji.
To add to the confusion the three mental patients also storm in to help the real Ashok and Kumar creating panic among the eyewitnesses on seeing so many lookalikes together. Movie closes with Ashok's father coming out of his coma and recognizing the true Ashok and getting Mamaji arrested for his deeds.
Saif Ali Khan is said to have drawn inspiration for his character from his real-life father-in-law Randhir Kapoor, and has hilariously brought to screen the quirky hand gestures and head movements that comprised Randhir Kapoor's 'style.'
Tamannaah Bhatia lost 5 Kgs for her role in Humshakals.
This contemporary comedy was extensively shot across exotic foreign locations, including the island of Mauritius.
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